WO2024163823A1

WO2024163823A1 - Tissue-specific enhancers for regulating transcription

Info

Publication number: WO2024163823A1
Application number: PCT/US2024/014116
Authority: WO
Inventors: Jacob Michael TOME; Richard Sullivan; Hussein AL-ASADI; Jennifer Eunmi MOON; Samantha Robin EDWARDS
Original assignee: Shape Therapeutics Inc
Current assignee: Shape Therapeutics Inc
Priority date: 2023-02-02
Filing date: 2024-02-01
Publication date: 2024-08-08
Anticipated expiration: 2025-08-02

Abstract

Described herein are sequences encoding an enhancer that enhances transcription of a payload under transcriptional control of the enhancer paired with a core promoter. In some embodiments, transcription of the payload may be enhanced in central nervous system tissues relative to non-central nervous system tissues, such as kidney tissues or liver tissues. In other embodiments, transcription of the payload may be enhanced in liver tissues relative to non-liver tissues, such as central nervous system tissues or kidney tissues. Also described herein are methods of expressing a payload in a target tissue, such as a target central nervous system tissue or a liver tissue, using a sequence encoding a tissue-specific enhancer.

Description

TISSUE-SPECIFIC ENHANCERS FOR REGULATING TRANSCRIPTION CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No.63/442,999, entitled “CNS-Specific Enhancers for Regulating Transcription,” filed February 2, 2023, U.S. Provisional Application No.63/459,916, entitled “CNS-Specific Enhancers for Regulating Transcription,” filed April 17, 2023, U.S. Provisional Application No.63/464,855, entitled “CNS-Specific Enhancers for Regulating Transcription,” filed May 8, 2023, U.S. Provisional Application No.63/531,243, entitled “CNS-Specific Enhancers for Regulating Transcription,” filed August 7, 2023, and U.S. Provisional Application No.63/543,671, entitled “CNS-Specific Enhancers for Regulating Transcription,” filed October 11, 2023, each of which applications are herein incorporated by reference in its entirety for all purposes. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in eXtensible Markup Language (XML) format and is hereby incorporated by reference in its entirety. Said XML copy, created on January 26, 2024, is named “421688- 718021_SL.xml” and is 409 kilobytes in size. BACKGROUND [0003] A wide variety of diseases and disorders are caused by mutations, deletions, or altered expression of genes. While substantial progress is being made toward delivery of transgenes into individuals for treatment of genetic disorders, there remains a need for gene therapies that can regulate transgene expression in a cell-type dependent manner. SUMMARY [0004] In various aspects, the present disclosure provides a recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter. [0005] In some aspects, the enhancer comprises a sequence having at least 90% sequence identity to SEQ ID NO: 4, or a reverse complement thereof. In some aspects, the enhancer comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof. [0006] In various aspects, the present disclosure provides a recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof; and a core promoter. [0007] In some aspects, the enhancer comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof. In some aspects, the enhancer comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof. [0008] In some aspects, the recombinant polynucleotide further comprises a payload, wherein: the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. In some aspects, the promoter enhances the transcription of the payload in a target tissue. In some aspects, the target tissue is a central nervous system tissue. In some aspects, the transcription is enhanced in the central nervous system tissue as compared to a kidney tissue. In some aspects, the transcription is enhanced in the central nervous system tissue as compared to a liver tissue, a heart tissue, a lung tissue, or a muscle tissue. [0009] In some aspects, the recombinant polynucleotide further comprises a post-transcriptional regulatory element. In some aspects, the recombinant polynucleotide further comprises a polyadenylation signal. In some aspects, the recombinant polynucleotide further comprises a transcriptional pause site. [0010] In various aspects, the present disclosure provides a recombinant polynucleotide comprising: a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof, and a core promoter capable of binding to a polymerase; a coding sequence operably linked to the promoter; a post-transcriptional regulatory element; a polyadenylation signal; and a transcriptional pause site. [0011] In some aspects, the enhancer comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 4, or a reverse complement thereof. In some aspects, the enhancer comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof. In some aspects, the coding sequence encodes a progranulin. -2- ^{Docket No. 421688-718021 (718WO1)} [0012] In some aspects, the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof. In some aspects, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366. In some aspects, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. In some aspects, the core promoter is a sequence of SEQ ID NO: 95. [0013] In some aspects, the post-transcriptional regulatory element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 287 or SEQ ID NO: 288. In some aspects, the post-transcriptional regulatory element comprises a sequence of SEQ ID NO: 288. In some aspects, the post-transcriptional regulatory element is downstream of the coding sequence. [0014] In some aspects, the polyadenylation signal comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. In some aspects, the polyadenylation signal comprises a sequence of SEQ ID NO: 299. In some aspects, the polyadenylation signal is downstream of the coding sequence. [0015] In some aspects, the transcriptional pause site comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 311. In some aspects, the transcriptional pause site comprises a sequence of SEQ ID NO: 311. In some aspects, the transcriptional pause site is downstream of the coding sequence. In some aspects, the transcriptional pause site is downstream of the polyadenylation signal. [0016] In some aspects, the coding sequence is downstream of the promoter, the post- transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post-transcriptional regulatory element, and the transcriptional pause site is downstream of the post-transcriptional regulatory element. In some aspects, the coding sequence is downstream of the promoter, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post- transcriptional regulatory element, and the transcriptional pause site is downstream of the polyadenylation signal. [0017] In some aspects, the recombinant polynucleotide further comprises a neuron-restrictive silencer element. In some aspects, the neuron-restrictive silencer element comprises at least -3- ^{Docket No. 421688-718021 (718WO1)} 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. [0018] In some aspects, the recombinant polynucleotide further comprises a CCCTC-binding factor sequence. In some aspects, the CCCTC-binding factor sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. [0019] In some aspects, the recombinant polynucleotide further comprises a stuffer sequence. In some aspects, the stuffer sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 309. In some aspects, the stuffer sequence comprises a sequence of SEQ ID NO: 309. In some aspects, the stuffer sequence is upstream of the coding sequence. In some aspects, the stuffer sequence is upstream of the promoter. [0020] In some aspects, the stuffer sequence is upstream of the promoter, the coding sequence is downstream of the promoter, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post-transcriptional regulatory element, and the transcriptional pause site is downstream of the polyadenylation signal. [0021] In some aspects, the recombinant polynucleotide further comprises a 5’ untranslated region. In some aspects, the 5’ untranslated region comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 310, SEQ ID NO: 353, or SEQ ID NO: 354. In some aspects, the 5’ untranslated region comprises a sequence of SEQ ID NO: 310. In some aspects, the 5’ untranslated region comprises a sequence of SEQ ID NO: 353. In some aspects, the 5’ untranslated region is upstream of the coding sequence. In some aspects, the 5’ untranslated region is downstream of the promoter. [0022] In some aspects, the stuffer sequence is upstream of the promoter, the 5’ untranslated region is downstream of the promoter, the coding sequence is downstream of the 5’ untranslated region, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post-transcriptional regulatory element, and the transcriptional pause site is downstream of the polyadenylation signal. [0023] In some aspects, the recombinant polynucleotide further comprises a 5’ inverted terminal repeat upstream of the promoter. In some aspects, the 5’ inverted terminal repeat is upstream of the stuffer sequence. In some aspects, the 5’ inverted terminal repeat is an AAV55’ inverted terminal repeat, an AAV15’ inverted terminal repeat, an AAV25’ inverted terminal repeat, an AAV95’ inverted terminal repeat, or a PhP.eB 5’ inverted terminal repeat. In some aspects, the -4- ^{Docket No. 421688-718021 (718WO1)} 5’ inverted terminal repeat is an AAV 5’ inverted terminal repeat. In some aspects, the AAV 5’ inverted terminal repeat is a single stranded AAV 5’ inverted terminal repeat. In some aspects, the 5’ inverted terminal repeat is an AAV25’ inverted terminal repeat. In some aspects, the AAV25’ inverted terminal repeat is a single stranded AAV25’ inverted terminal repeat. In some aspects, the 5’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 307. In some aspects, the 5’ inverted terminal repeat comprises a sequence of SEQ ID NO: 307. [0024] In some aspects, the recombinant polynucleotide further comprises a 3’ inverted terminal repeat downstream of the transcriptional pause site. In some aspects, the 3’ inverted terminal repeat is an AAV 3’ inverted terminal repeat. In some aspects, the AAV 3’ inverted terminal repeat is a single stranded AAV 3’ inverted terminal repeat. In some aspects, the 3’ inverted terminal repeat is an AAV53’ inverted terminal repeat, an AAV13’ inverted terminal repeat, an AAV23’ inverted terminal repeat, an AAV93’ inverted terminal repeat, or a PhP.eB 3’ inverted terminal repeat. In some aspects, the 3’ inverted terminal repeat is an AAV23’ inverted terminal repeat. In some aspects, the AAV23’ inverted terminal repeat is a single stranded AAV23’ inverted terminal repeat. In some aspects, the 3’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 308. In some aspects, the 3’ inverted terminal repeat comprises a sequence of SEQ ID NO: 308. [0025] In some aspects, the 5’ inverted terminal repeat is upstream of the stuffer sequence, the stuffer sequence is upstream of the promoter, the 5’ untranslated region is downstream of the promoter, the coding sequence is downstream of the 5’ untranslated region, the post- transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post-transcriptional regulatory element, the transcriptional pause site is downstream of the polyadenylation signal, and the 3’ inverted terminal repeat downstream of the transcriptional pause site. [0026] In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4 and (ii) SEQ ID NO 95. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; and (iii) SEQ ID NO: 350. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; and (iv) SEQ ID NO: 288. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; and (iv) SEQ ID NO: 299. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; (iv) SEQ ID NO: -5- ^{Docket No. 421688-718021 (718WO1)} 288; and (v) SEQ ID NO: 299. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; and (iv) SEQ ID NO: 311. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; (iv) SEQ ID NO: 288; (v) SEQ ID NO: 299; and (vi) SEQ ID NO: 311. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 353; (iv) SEQ ID NO: 350; (v) SEQ ID NO: 288; (vi) SEQ ID NO: 299; and (vii) SEQ ID NO: 311. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; and (iii) SEQ ID NO: 353. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; and (v) SEQ ID NO: 350. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; and (vii) SEQ ID NO: 299. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; and (vi) SEQ ID NO: 311. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; (vii) SEQ ID NO: 299; and (viii) SEQ ID NO: 311. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 309; (iii) SEQ ID NO: 4; (iv) SEQ ID NO 95; (v) SEQ ID NO: 353; (vi) SEQ ID NO: 350; (vii) SEQ ID NO: 288; (viii) SEQ ID NO: 299; (ix) SEQ ID NO: 311; and (x) SEQ ID NO: 308. [0027] In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; and (iii) SEQ ID NO: 308. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; and (iv) SEQ ID NO: 308. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 350; and (v) SEQ ID NO: 308. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; and (vi) SEQ ID NO: 308. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; (vii) SEQ ID NO: 299; and (viii) SEQ ID NO: 308. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 311; and (vii) SEQ ID NO: 308. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; -6- ^{Docket No. 421688-718021 (718WO1)} (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; (vii) SEQ ID NO: 299; (viii) SEQ ID NO: 311; and (ix) SEQ ID NO: 308. In some aspects, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 309; (iii) SEQ ID NO: 4; (iv) SEQ ID NO 95; (v) SEQ ID NO: 353; (vi) SEQ ID NO: 350; (vii) SEQ ID NO: 288; (viii) SEQ ID NO: 299; (ix) SEQ ID NO: 311; and (x) SEQ ID NO: 308. [0028] In some aspects, the recombinant polynucleotide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 312. In some aspects, the recombinant polynucleotide comprises a sequence having at least 80% sequence identity to SEQ ID NO: 312. In some aspects, the recombinant polynucleotide comprises a sequence having at least 90% sequence identity to SEQ ID NO: 312. In some aspects, the recombinant polynucleotide comprises a sequence of SEQ ID NO: 312. In some aspects, the recombinant polynucleotide is SEQ ID NO: 312. [0029] In some aspects, the payload encodes a protein; optionally, wherein the protein is a therapeutic protein. In some aspects, the protein is a neuronal protein or an antibody; optionally, wherein the antibody is a therapeutic antibody. In some aspects, the protein is associated with a central nervous system disorder. In some aspects, the central nervous system disorder is a neuronal disorder. In some aspects, the central nervous system disorder is a genetic disorder. In some aspects, the protein is progranulin or MeCP2. In some aspects, the progranulin is human progranulin. [0030] In some aspects, the progranulin encoded by the payload comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 352. In some aspects, the payload comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 350. In some aspects, the payload comprises a sequence of SEQ ID NO: 350. [0031] In some aspects, the payload encodes a therapeutic polynucleotide. In some aspects, the therapeutic polynucleotide is a guide RNA or a suppressor tRNA. In some aspects, the therapeutic polynucleotide targets a gene. In some aspects, the gene is associated with a central nervous system disorder. In some aspects, the central nervous system disorder is a neuronal disorder. In some aspects, the central nervous system disorder is a genetic disorder. In some aspects, the gene is GRN or MECP2. [0032] In various aspects, the present disclosure provides a plasmid comprising the recombinant polynucleotide as described herein. -7- ^{Docket No. 421688-718021 (718WO1)} [0033] In some aspects, the plasmid comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 355. [0034] In various aspects, the present disclosure provides an engineered viral vector comprising the recombinant polynucleotide as described herein. [0035] In some aspects, the viral vector is an adenoviral vector, an adeno-associated viral vector, or a lentivector. In some aspects, the adeno-associated viral vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV-DJ, AAV-DJ/8, AAV-DJ/9, AAV1/2, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh43, AAV.Rh74, AAV.v66, AAV.Oligo001, AAV.SCH9, AAV.r3.45, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PhP.eB, AAV.PhP.V1, AAV.PHP.B, AAV.PhB.C1, AAV.PhB.C2, AAV.PhB.C3, AAV.PhB.C6, AAV.cy5, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAV.HSC17, AAVhu68, and combinations thereof. In some aspects, the adeno-associated viral vector is an AAV5 vector. In some aspects, the adeno-associated viral vector comprises an engineered viral protein (VP) capsid polypeptide. In some aspects, the engineered VP capsid polypeptide comprises at least one substitution in a VR VIII loop of an AAV. In some aspects, the engineered VP capsid polypeptide comprises at least one substitution in a region of the engineered VP capsid polypeptide corresponding to a 581-589 region of a wild type VP capsid polypeptide of SEQ ID NO: 313. In some aspects, the engineered VP capsid polypeptide comprises a formula of (A)-(X)-(B), wherein (A) is a first polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 318, (X) is the 581-589 region, and (B) is a second polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 319. [0036] In various aspects, the present disclosure provides a pharmaceutical composition comprising the recombinant polynucleotide as described herein, the plasmid as described herein, or the engineered viral vector as described herein and a pharmaceutically acceptable carrier. [0037] In various aspects, the present disclosure provides a method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide to the target cell or the target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence -8- ^{Docket No. 421688-718021 (718WO1)} identity to SEQ ID NO: 4, or a reverse complement thereof, and a payload operably linked to the enhancer; and transcribing the payload in the target cell or the target tissue. [0038] In various aspects, the present disclosure provides a method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide comprising a promoter to the target cell or the target tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter; and transcribing the payload in the target cell or the target tissue. [0039] In various aspects, the present disclosure provides a method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide to the target cell or the target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, and a payload operably linked to the enhancer; and transcribing the payload in the target cell or the target tissue. [0040] In various aspects, the present disclosure provides a method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide comprising a promoter to the target cell or the target tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof; and a core promoter; and transcribing the payload in the target cell or the target tissue. [0041] In some aspects, the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof. In some aspects, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366. In some aspects, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. In some aspects, the core promoter is a sequence of SEQ ID NO: 95. [0042] In some aspects, the recombinant polynucleotide is the recombinant polynucleotide as described herein, or the recombinant polynucleotide as described herein or in the engineered viral vector as described herein. In some aspects, the method further comprises delivering the -9- ^{Docket No. 421688-718021 (718WO1)} recombinant polynucleotide by administering the pharmaceutical composition as described herein to the subject. [0043] In some aspects, the target tissue is a central nervous system tissue. In some aspects, the method comprises expressing the payload at a higher level in the target tissue than in a non- target tissue. In some aspects, the non-target tissue is a kidney tissue, a liver tissue, a heart tissue, a lung tissue, or a muscle tissue. In some aspects, the target tissue comprises a target cell type, and wherein the non-target tissue comprises a non-target cell type. In some aspects, the target cell type is a neuron or a glial cell. In some aspects, the non-target cell type is a renal cell, a retinal cell, a hepatocyte, an epithelial cell, a muscle cell, an erythrocyte, a platelet, a bone marrow cell, an endothelial cell, an epidermal cell, a lymphocyte, an interstitial cell, an adipocyte, a fibroblast, or combinations thereof. [0044] In some aspects, the payload encodes for progranulin. In some aspects, the progranulin is human progranulin. In some aspects, the method comprises expressing the progranulin in a fluid secreted by the cell, tissue, or subject. In some aspects, the progranulin is expressed in the fluid at a level of not less than 1 ng/mL and not more than 100 ng/mL. In some aspects, the progranulin is expressed in the fluid at a level of not less than 10 ng/mL and not more than 100 ng/mL. In some aspects, the progranulin is expressed in the fluid at a level of not less than 1 ng/mL and not more than 30 ng/mL. In some aspects, the progranulin is expressed in the fluid at a level of not less than 10 ng/mL and not more than 50 ng/mL. In some aspects, the progranulin is expressed in the fluid at a level of not less than 10 ng/mL and not more than 30 ng/mL. In some aspects, the progranulin is expressed in the fluid at a level of not less than 70 ng/mL and not more than 180 ng/mL. In some aspects, the progranulin is expressed in the fluid at a level of not less than 70 ng/mL and not more than 300 ng/mL. In some aspects, the fluid comprises a cerebrospinal fluid. [0045] In various aspects, the present disclosure provides a method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide to a target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof, and a payload operably linked to the enhancer; and expressing a therapeutic sequence encoded by the payload in a target tissue of the subject, thereby treating the disorder. [0046] In various aspects, the present disclosure provides a method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide comprising a promoter to the target cell or the target -10- ^{Docket No. 421688-718021 (718WO1)} tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter; and expressing a therapeutic sequence encoded by the payload in a target tissue of the subject, thereby treating the disorder. [0047] In various aspects, the present disclosure provides a method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide to a target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, and a payload operably linked to the enhancer; and expressing a therapeutic sequence encoded by the payload in a target tissue of the subject, thereby treating the disorder. [0048] In various aspects, the present disclosure provides a method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide comprising a promoter to the target cell or the target tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof; and a core promoter; and expressing a therapeutic sequence encoded by the payload in a target tissue of the subject, thereby treating the disorder. [0049] In some aspects, the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof. In some aspects, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366. In some aspects, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. In some aspects, the core promoter is a sequence of SEQ ID NO: 95. [0050] In some aspects, the recombinant polynucleotide as described herein, or the recombinant polynucleotide is in the plasmid as described herein or in the engineered viral vector as described herein. In some aspects, the composition is the pharmaceutical composition as described herein. -11- ^{Docket No. 421688-718021 (718WO1)} [0051] In some aspects, the target tissue is associated with the disorder. In some aspects, the disorder is a central nervous system disorder. In some aspects, the central nervous system disorder is a neuronal disorder. In some aspects, the central nervous system disorder is a genetic disorder. In some aspects, the disorder is Rett syndrome, MECP2 duplication syndrome, frontotemporal dementia, neuronal ceroid lipofuscinosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson’s disease. In some aspects, the disorder is frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease, Parkinson’s Disease, stroke, Gaucher disease, arthritis, limbic-predominant age-related transactivation response DNA-binding protein 43 (TDP-43) encephalopathy, autism, neuronal ceroid lipofuscinosis (e.g., type 11 (CLN11)), dementia, and neurodegeneration; optionally, wherein the neuronal ceroid lipofuscinosis is type 11; optionally, wherein neurodegeneration is neurodegeneration associated with normal aging. In some aspects, the disorder is frontotemporal dementia. In some aspects, the disorder is any one of the disorders provided in TABLE 3. [0052] In some aspects, the therapeutic sequence encodes a therapeutic protein. In some aspects, the therapeutic protein is a neuronal protein or an antibody. In some aspects, the therapeutic protein is associated with a central nervous system disorder. In some aspects, the central nervous system disorder is a neuronal disorder. In some aspects, the central nervous system disorder is a genetic disorder. In some aspects, the therapeutic protein is MECP2 or progranulin. In some aspects, the therapeutic protein is encoded by a gene provided in TABLE 3. [0053] In some aspects, the payload encodes a therapeutic polynucleotide. In some aspects, the therapeutic polynucleotide is a guide RNA or a suppressor tRNA. In some aspects, the therapeutic polynucleotide targets a gene provided in TABLE 3. [0054] In various aspects, the present disclosure provides a method of treating frontotemporal dementia in a subject having frontotemporal dementia, the method comprising: delivering a recombinant polynucleotide comprising an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof, and a coding sequence operably linked to the enhancer, to the subject having frontotemporal dementia; and expressing a progranulin encoded by the coding sequence, thereby treating the subject. [0055] In various aspects, the present disclosure provides a method of treating frontotemporal dementia in a subject having frontotemporal dementia, the method comprising: delivering a recombinant polynucleotide comprising an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof, a core promoter, and a coding sequence operably linked to the enhancer and the core promoter, to the subject having -12- ^{Docket No. 421688-718021 (718WO1)} frontotemporal dementia; and expressing a progranulin encoded by the coding sequence, thereby treating the subject. [0056] In various aspects, the present disclosure provides a method of treating frontotemporal dementia in a subject having frontotemporal dementia, the method comprising: delivering the recombinant polynucleotide as described herein, the recombinant polynucleotide in the plasmid as described herein or in the viral vector as described herein, or the pharmaceutical composition as described herein to the subject having frontotemporal dementia, thereby treating the frontotemporal dementia. [0057] In some aspects, the enhancer is a sequence of SEQ ID NO: 4. In some aspects, In some aspects, the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof. In some aspects, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366. In some aspects, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. In some aspects, the core promoter is a sequence of SEQ ID NO: 95. [0058] In some aspects, the method comprises expressing the progranulin in a cerebrospinal fluid of the subject. In some aspects, the progranulin is expressed in the cerebrospinal fluid at a level of not less than 10 ng/mL and not more than 100 ng/mL. In some aspects, the progranulin is expressed in the cerebrospinal fluid at a level of not less than 1 ng/mL and not more than 100 ng/mL. In some aspects, the progranulin is expressed in the cerebrospinal fluid at a level of not less than 10 ng/mL and not more than 30 ng/mL. In some aspects, the progranulin is expressed in the cerebrospinal fluid at a level of not less than 1 ng/mL and not more than 30 ng/mL. In some aspects, the progranulin is expressed in the cerebrospinal fluid at a level of not less than 10 ng/mL and not more than 50 ng/mL. In some aspects, the progranulin is expressed in the cerebrospinal fluid at a level of not less than 10 ng/mL and not more than 30 ng/mL. In some aspects, the progranulin is expressed in the cerebrospinal fluid at a level of not less than 70 ng/mL and not more than 180 ng/mL. In some aspects, the progranulin is expressed in the cerebrospinal fluid at a level of not less than 70 ng/mL and not more than 300 ng/mL. [0059] In some aspects, an expression level of the progranulin in a serum of the subject is not more than 100-fold, not more than 50-fold, not more than 25-fold, not more than 20-fold, or not more than 10-fold an expression level of the progranulin in the cerebrospinal fluid. In some aspects, an expression level of the progranulin in a serum of the subject is not less than 0.01- -13- ^{Docket No. 421688-718021 (718WO1)} fold, not less than 0.05-fold, not less than 0.1-fold, not less than 0.2-fold, not less than 0.25-fold, or not less than 0.5-fold an expression level of the progranulin in the cerebrospinal fluid. In some aspects, an expression level of the progranulin in a serum of the subject is not more than 300 ng/mL. In some aspects, an expression level of the progranulin in a serum of the subject is not more than 1500 ng/mL. [0060] In some aspects, the subject is a mammal. In some aspects, the mammal is a human, a non-human primate, a rat, a rabbit, a mouse, or a guinea pig. In some aspects, the delivering comprises intravenous administration. [0061] In various aspects, the present disclosure provides a recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof; and a core promoter. [0062] In some aspects, the enhancer comprises a sequence having at least 90% sequence identity to SEQ ID NO: 362, or a reverse complement thereof. In some aspects, the enhancer comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 362, or a reverse complement thereof. [0063] In some aspects, the recombinant polynucleotide further comprises a payload, wherein: the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. [0064] In some aspects, the promoter enhances the transcription of the payload in a target tissue. In some aspects, the target tissue is liver tissue. In some aspects, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. In some aspects, the payload encodes a protein; optionally, wherein the protein is a therapeutic protein. In some aspects, the protein is a liver protein or an antibody; optionally, wherein the antibody is a therapeutic antibody. In some aspects, the protein is associated with a liver disorder. [0065] In various aspects, the present disclosure provides a method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide to the target cell or the target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof, and a payload operably linked to the enhancer; and transcribing the payload in the target cell or the target tissue. -14- ^{Docket No. 421688-718021 (718WO1)} [0066] In various aspects, the present disclosure provides a method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide to a target cell or a target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof, and a payload operably linked to the enhancer; and expressing a therapeutic sequence encoded by the payload in the target cell or the target tissue of the subject, thereby treating the disorder. [0067] In some aspects, the disorder is a liver disorder. In some aspects, the therapeutic sequence encodes a therapeutic protein. [0068] In various aspects, the present disclosure provides a recombinant polynucleotide comprising a promoter and a payload, wherein the promoter comprises: an enhancer capable of enhancing transcription of the payload in a tissue of interest; and a core promoter capable of binding to a polymerase; wherein the payload comprises a coding sequence encoding a protein. [0069] In some aspects, the tissue of interest is a central nervous system tissue. In some aspects, the transcription is enhanced in the central nervous system tissue as compared to a kidney tissue. In some aspects, the transcription is enhanced in the central nervous system tissue as compared to a liver tissue, a heart tissue, a lung tissue, or a muscle tissue. [0070] In some aspects, the enhancer comprises a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof. In some aspects, the enhancer comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof. In some aspects, the enhancer comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer. In some aspects, the enhancer comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof. In some aspects, the enhancer comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof. In some aspects, the enhancer comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, -15- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer. In some aspects, the enhancer comprises any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof. In some aspects, the enhancer comprises one or more enhancer sequences selected from SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof. In some aspects, the enhancer comprises one or more enhancer sequences selected from SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer. [0071] In some aspects, the enhancer comprises SEQ ID NO: 1, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 2, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 3, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 4, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 5, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 6, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 7, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 8, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 9, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 10, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 11, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 12, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 13, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 14, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 15, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 16, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 17, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 18, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 19, or a reverse complement thereof. In some aspects, the enhancer comprises SEQ ID NO: 20, or a reverse complement thereof. [0072] In some aspects, the enhancer comprises two or more of SEQ ID NO: 1 – SEQ ID NO: 20. In some aspects, the enhancer comprises any one of SEQ ID NO: 237 – SEQ ID NO: 266. In -16- ^{Docket No. 421688-718021 (718WO1)} some aspects, the enhancer comprises SEQ ID NO: 244. In some aspects, the enhancer comprises a duplication of any one of SEQ ID NO: 1 – SEQ ID NO: 20. In some aspects, the enhancer comprises any one of SEQ ID NO: 267 – SEQ ID NO: 286. [0073] In some aspects, the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, or a YB_TATA promoter. In some aspects, the core promoter comprises any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366. In some aspects, the core promoter comprises SEQ ID NO: 95. [0074] In some aspects, the recombinant polynucleotide further comprises a post-transcriptional regulatory element. In some aspects, the post-transcriptional regulatory element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 287 or SEQ ID NO: 288. [0075] In some aspects, the recombinant polynucleotide further comprises a neuron-restrictive silencer element. In some aspects, the neuron-restrictive silencer element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. [0076] In some aspects, the recombinant polynucleotide further comprises a polyadenylation signal. In some aspects, the polyadenylation signal comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. [0077] In some aspects, the recombinant polynucleotide further comprises a transcriptional pause site. In some aspects, the transcriptional pause site comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 311. [0078] In some aspects, the recombinant polynucleotide further comprises a CCCTC-binding factor sequence. In some aspects, the CCCTC-binding factor sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. [0079] In some aspects, the recombinant polynucleotide further comprises a stuffer sequence. In some aspects, the stuffer sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 309. [0080] In some aspects, the recombinant polynucleotide comprises a 5’ untranslated region. In some aspects, the 5’ untranslated region comprises at least 80%, at least 85%, at least 90%, at -17- ^{Docket No. 421688-718021 (718WO1)} least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 310, SEQ ID NO: 353, or SEQ ID NO: 354. [0081] In some aspects, the recombinant polynucleotide further comprises a 5’ inverted terminal repeat. In some aspects, the 5’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 307. [0082] In some aspects, the recombinant polynucleotide further comprises a 3’ inverted terminal repeat. In some aspects, the 3’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 308. [0083] In some aspects, the recombinant polynucleotide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 312. [0084] In some aspects, the payload encodes a protein. In some aspects, the protein is a neuronal protein or an antibody; optionally, wherein the antibody is a therapeutic antibody. In some aspects, the protein is associated with a central nervous system disorder. In some aspects, the central nervous system disorder is a neuronal disorder. In some aspects, the central nervous system disorder is a genetic disorder. In some aspects, the protein is progranulin or MeCP2. In some aspects, the progranulin encoded by the payload comprises at least 90% sequence identity to SEQ ID NO: 352. In some aspects, the progranulin is encoded by a payload comprising a sequence with at least 90% sequence identity to SEQ ID NO: 350. [0085] In some aspects, the payload encodes a therapeutic polynucleotide. In some aspects, the therapeutic polynucleotide is a guide RNA or a suppressor tRNA. In some aspects, the therapeutic polynucleotide targets a gene. In some aspects, the gene is associated with a central nervous system disorder. In some aspects, the central nervous system disorder is a neuronal disorder. In some aspects, the central nervous system disorder is a genetic disorder. In some aspects, the gene is GRN or MECP2. [0086] In various aspects, the present disclosure provides a plasmid comprising a recombinant polynucleotide as described herein. [0087] In some aspects, the plasmid comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 355. -18- ^{Docket No. 421688-718021 (718WO1)} [0088] In various aspects, the present disclosure provides an engineered viral vector comprising a recombinant polynucleotide as described herein or a plasmid as described herein in a viral vector. [0089] In some aspects, the viral vector is an adenoviral vector, an adeno-associated viral vector, or a lentivector. In some aspects, the adeno-associated viral vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV-DJ, AAV-DJ/8, AAV-DJ/9, AAV1/2, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh43, AAV.Rh74, AAV.v66, AAV.Oligo001, AAV.SCH9, AAV.r3.45, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PhP.eB, AAV.PhP.V1, AAV.PHP.B, AAV.PhB.C1, AAV.PhB.C2, AAV.PhB.C3, AAV.PhB.C6, AAV.cy5, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAV.HSC17, AAVhu68, and combinations thereof. In some aspects, the adeno-associated viral vector is an AAV5 vector. [0090] In some aspects, the adeno-associated viral vector comprises an engineered viral protein (VP) capsid polypeptide. In some aspects, the engineered VP capsid polypeptide comprises at least one substitution in a 581-589 region of the engineered VP capsid polypeptide relative to a wild type VP capsid polypeptide of SEQ ID NO: 313. In some aspects, the 581-589 region comprises a sequence of any one of SEQ ID NO: 320 – SEQ ID NO: 349. In some aspects, the 581-589 region comprises a sequence of SEQ ID NO: 320. In some aspects, the 581-589 region comprises a sequence of SEQ ID NO: 321. In some aspects, the 581-589 region comprises a sequence of SEQ ID NO: 322. In some aspects, the 581-589 region comprises a sequence of SEQ ID NO: 334. In some aspects, the engineered VP capsid polypeptide comprises a formula of (A)-(X)-(B), wherein (A) is a first polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 318, (X) is the 581-589 region, and (B) is a second polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 319. [0091] In various aspects, the present disclosure provides a pharmaceutical composition comprising a recombinant polynucleotide as described herein, a plasmid as described herein, or an engineered viral vector as described herein and a pharmaceutically acceptable carrier. [0092] In various aspects, the present disclosure provides a method of expressing a payload in a target tissue of a subject, the method comprising: administering to the subject a recombinant polynucleotide as described herein, a plasmid as described herein, an engineered viral vector as -19- ^{Docket No. 421688-718021 (718WO1)} described herein, or a pharmaceutical composition as described herein to the subject; and transcribing the payload in the target tissue. The method of expressing a payload in a target tissue of a subject can result in treating a disease or disorder as described herein. The method of expressing a payload in a tissue may be conducted in vitro, ex vivo or in vivo. [0093] In some aspects, the target tissue is a central nervous system tissue. In some aspects, the method comprises expressing the payload at a higher level in the target tissue than in a non- target tissue. In some aspects, the non-target tissue is a kidney tissue, a liver tissue, a heart tissue, a lung tissue, or a muscle tissue. In some aspects, the target tissue a target cell type, and wherein the non-target tissue comprises a non-target cell type. In some aspects, the target cell type is a neuron or a glial cell. In some aspects, the non-target cell type is a renal cell, a retinal cell, a hepatocyte, an epithelial cell, a muscle cell, an erythrocyte, a platelet, a bone marrow cell, an endothelial cell, an epidermal cell, a lymphocyte, an interstitial cell, an adipocyte, a fibroblast, or combinations thereof. [0094] In various aspects, the present disclosure provides a method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide as described herein, a plasmid as described herein, an engineered viral vector as described herein, or a pharmaceutical composition as described herein to the subject; and expressing a therapeutic sequence encoded by a payload of the recombinant polynucleotide in a target tissue of the subject, thereby treating the disorder. [0095] In various aspects, the present disclosure provides a recombinant polynucleotide for use as a medicament. In various aspects, the present disclosure provides a recombinant polynucleotide for use in a method of treating a disease or disorder. In various aspects, the present disclosure provides use of a substance or composition, wherein the substance or composition is a recombinant polynucleotide as described herein, a plasmid as described herein, an engineered viral vector as described herein, or a pharmaceutical composition as described herein for the manufacture of a medicament for therapeutic applications. In some embodiments, the therapeutic application is a CNS diseases or disorders. [0096] In some aspects, the target tissue is associated with the disorder. In some aspects, the disorder is a central nervous system disorder. In some aspects, the central nervous system disorder is a neuronal disorder. In some aspects, the central nervous system disorder is a genetic disorder. In some aspects, the disorder is Rett syndrome, MECP2 duplication syndrome, frontotemporal dementia, neuronal ceroid lipofuscinosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson’s disease. In some aspects, the disorder is any one of the disorders provided in TABLE 3. -20- ^{Docket No. 421688-718021 (718WO1)} [0097] In some aspects, the therapeutic sequence encodes a therapeutic protein. In some aspects, the therapeutic protein is a neuronal protein or an antibody. In some aspects, the therapeutic protein is associated with a central nervous system disorder. In some aspects, the central nervous system disorder is a neuronal disorder. In some aspects, the central nervous system disorder is a genetic disorder. In some aspects, the therapeutic protein is MECP2 or progranulin. In some aspects, the therapeutic protein is encoded by a gene provided in TABLE 3. [0098] In some aspects, the payload encodes a therapeutic polynucleotide. In some aspects, the therapeutic polynucleotide is a guide RNA or a suppressor tRNA. In some aspects, the therapeutic polynucleotide targets a gene provided in TABLE 3. INCORPORATION BY REFERENCE [0099] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS [0100] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [0101] FIG.1 shows a profile of a candidate enhancer corresponding to an enhancer near opioid-binding protein/cell adhesion molecule (OPCML). Row 1 shows chromatin accessibility in excitatory neurons; Row 2 shows chromatin accessibility in cerebellar astrocytes; Row 3 shows chromatin accessibility in cerebellar vascular endothelial cells; Row 4 shows chromatin accessibility in cerebellar astrocytes; Row 5 shows chromatin accessibility in liver hepatocytes; Row 6 shows chromatin accessibility in liver myeloid cells; Rows 7 and 8 show chromatin accessibility in LUHMES-derived neurons; Row 9 shows sequence conservation across vertebrates; Row 10 shows H3K27ac epigenetic modifications in brain tissue derived from a human donor; Row 11 show a narrowed candidate enhancer; Row 12 shows a 170 base region selected for inclusion in the library in which the final promoter sequence comprises this 170 base region and a core promoter sequence. -21- ^{Docket No. 421688-718021 (718WO1)} [0102] FIG.2 shows a plot of tissue-specific transcription, in transcripts per million (TPM), of neuronal marker gene opioid-binding protein/cell adhesion molecule (OPCML) controlled by a candidate enhancer. The neuronal marker gene exhibited neuronal tissue-specific expression. [0103] FIG.3 schematically illustrates a method of preparing an enhancer/promoter (e.g., enhancer/core promoter) library for screening in cells using a massively parallel reporter assay. Enhancers are designed to form a library of candidate enhancers. Each candidate enhancer is paired with a core promoter, a random barcode sequence, an intron, and reporter ORF (such as GFP), in a construct that is cloned into a carrier plasmid to generate a library of candidate enhancer plasmids for subsequent testing in various models. The carrier plasmid can be a transfection plasmid, a lentiviral transfer plasmid, or a plasmid for producing AAV virion that delivers the construct into cells. Next generation sequencing is used to associate each candidate enhancer with its corresponding random barcode sequence and assess promoter activity. [0104] FIG.4A shows a scatter plot of transcription activity (log RNA / DNA) for enhancers in mouse primary neurons as compared to a HepG2 liver cell line. Central nervous system (CNS) enhancers, represented by black circles, exhibit higher transcription in neurons than in liver cells. [0105] FIG.4B shows a scatter plot of transcription activity (log RNA / DNA) for enhancers in Lund human mesencephalic (LUHMES) cells as compared to a HepG2 liver cell line. LUHMES cells are human embryonic neuronal precursor cells. Central nervous system (CNS) enhancers, represented by black circles, exhibit higher transcription in the neuronal precursor cells than in liver cells. [0106] FIG.4C shows a scatter plot of transcription activity (log RNA / DNA) for enhancers in mouse brain tissue as compared to mouse liver tissue. Central nervous system (CNS) enhancers, represented by black circles, exhibit higher transcription in brain tissue than in liver tissue. [0107] FIG.5 shows scatter plots of transcription activity (log RNA / DNA) for enhancers in mouse brain tissue as compared to mouse liver tissue in five different mice. Candidate CNS- specific enhancers are represented by larger gray points. [0108] FIG.6 shows scatter plots of transcription activity (log RNA / DNA) for enhancers in mouse brain tissue as compared to mouse heart, kidney, leg-muscle (gastrocnemius), liver, and lung tissues. Top candidate CNS-specific enhancers are represented by black points. [0109] FIG.7A shows scatter plots of transcription activity (log RNA / DNA) for enhancers in LUHMES embryonic neuronal precursor cells as compared to H4 neuroglioma cells, as compared to HepG2 hepatoma cells, as compared to K562 lymphoblasts, and as compared to -22- ^{Docket No. 421688-718021 (718WO1)} mouse primary neuronal cells (“mice-neuron”). Top candidate CNS-specific enhancers are represented by larger gray points. [0110] FIG.7B shows scatter plots of transcription activity (log RNA / DNA) for enhancers in mouse primary neuronal cells (“mice-neuron”) as compared to LUHMES embryonic neuronal precursor cells, H4 neuroglioma cells, HepG2 hepatoma cells, and K562 lymphoblasts. Top candidate CNS-specific enhancers are represented by larger gray points. [0111] FIG.8A shows a scatter plot of transcription activity (log RNA / DNA) for enhancers in mouse brain tissue as compared to mouse liver tissue. Candidate CNS-specific enhancers (“LUHMES Candidates”) are represented by the indicated points to the left of the dashed line, and candidate liver-specific enhancers (“HepG2 validated”) are represented by the indicated points to the right of the dashed line. A positive control construct is indicated with an asterisk (*). [0112] FIG.8B shows a scatter plot of transcription activity (log RNA / DNA) for enhancers in LUHMES embryonic neuronal precursor cells as compared to HepG2 hepatoma cells. Candidate CNS-specific enhancers (“LUHMES Candidates”) are represented by the indicated points to the left of the dashed line, and candidate liver-specific enhancers (“HepG2 validated”) are represented by the indicated points to the right of the dashed line. A positive control construct is indicated with an asterisk (*). [0113] FIG.8C shows a scatter plot of transcription activity (log RNA / DNA) for enhancers in mouse primary neurons as compared to mouse liver tissue. Candidate CNS-specific enhancers (“LUHMES Candidates”) are represented by the indicated points to the left of the dashed line, and candidate liver-specific enhancers (“HepG2 validated”) are represented by the indicated points to the right of the dashed line. A positive control construct is indicated with an asterisk (*). [0114] FIG.9A shows a scatter plot of transcription activity (log RNA / DNA) for enhancers in mouse brain tissue as compared to mouse primary neurons. Candidate CNS-specific enhancers (“LUHMES Candidates”) are represented by the indicated points, and candidate liver-specific enhancers (“HepG2 validated”) are represented by the indicated points. A positive control construct is indicated with an asterisk (*). [0115] FIG.9B shows a scatter plot of transcription activity (log RNA / DNA) for enhancers in mouse brain tissue as compared to LUHMES embryonic neuronal precursor cells. Candidate CNS-specific enhancers (“LUHMES Candidates”) are represented by the indicated points, and -23- ^{Docket No. 421688-718021 (718WO1)} candidate liver-specific enhancers (“HepG2 validated”) are represented by the indicated points. A positive control construct is indicated with an asterisk (*). [0116] FIG.9C shows a scatter plot of transcription activity (log RNA / DNA) for enhancers in mouse primary neurons as compared to LUHMES embryonic neuronal precursor cells. Candidate CNS-specific enhancers (“LUHMES Candidates”) are represented by the indicated points, and candidate liver-specific enhancers (“HepG2 validated”) are represented by the indicated points. A positive control construct is indicated with an asterisk (*). [0117] FIG.10 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 1 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0118] FIG.11 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 2 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0119] FIG.12 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 3 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0120] FIG.13 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 4 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0121] FIG.14 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 5 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0122] FIG.15 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 6 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0123] FIG.16 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 7 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0124] FIG.17 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 8 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0125] FIG.18 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 9 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0126] FIG.19 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 10 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0127] FIG.20 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 11 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0128] FIG.21 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 12 in mouse brain, heart, kidney, liver, lung, and muscle tissues. -24- ^{Docket No. 421688-718021 (718WO1)} [0129] FIG.22 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 13 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0130] FIG.23 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 14 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0131] FIG.24 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 15 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0132] FIG.25 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 16 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0133] FIG.26 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 17 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0134] FIG.27 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 18 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0135] FIG.28 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 19 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0136] FIG.29 shows a violin plot of the transcription activity (“lr”) of a CNS-specific enhancer of SEQ ID NO: 20 in mouse brain, heart, kidney, liver, lung, and muscle tissues. [0137] FIG.30 shows scatter plots of transcription activity (log RNA / DNA) for enhancers in mouse brain tissue as compared to mouse liver, lung, muscle, and heart tissues. Top candidate CNS-specific enhancers are represented by the darkest shaded points. [0138] FIG.31A shows a bar plot of expression of a progranulin payload (“GRN expression”) encoded by expression constructs containing either a constitutive promoter, a CNS-specific promoter containing a CNS-enhancer (“novel CNS promoters”), or a negative control promoter (“scrambled control”) in mouse primary neurons. [0139] FIG.31B shows a bar plot of expression of a progranulin payload (“GRN expression”) encoded by expression constructs containing either a constitutive promoter, a CNS-specific promoter containing a CNS-enhancer (“novel CNS promoters”), or a negative control promoter (“scrambled control”) in HepG2 cells. [0140] FIG.32 schematically illustrates a dual expression cassette for comparing enhancer activity across cell populations. The dual expression cassette includes two expression constructs, one encoding a human progranulin (“hPGRN”) under control of an enhancer (e.g., any of SEQ ID NO: 1 – SEQ ID NO: 20) and a minP variant core promoter of SEQ ID NO: 95 (“Enhancer + minP”) with a WPRE3 regulatory element and a polyA sequence, and a second encoding -25- ^{Docket No. 421688-718021 (718WO1)} luciferase (“s_nLuciferase”) under control of a CMV promoter with a polyA sequence. The two expression constructs are separated by an insulator to prevent readthrough. [0141] FIG.33A shows a bar plot of enhancer specificity in either human induced pluripotent stem cell derived neurons (iPSC; solid line bars) or mouse primary neurons (MPN; dashed line bars) relative to HepG2 liver cells. Specificity was determined by comparing expression levels of hPGRN under control of an enhancer of each of SEQ ID NO: 1 – SEQ ID NO: 20, an RSV promoter, a human synapsin promoter (“hSyn”), or a scrambled promoter (“scrambled”) in neuronal cells (iPSC or MPN) versus liver cells (HepG2) using the dual cassette illustrated in FIG.32. Cells that were not transduced with virus (“no virus”) were included as a negative control. Progranulin expression was normalized to luciferase expression to account for differences in transduction efficiency. High specificity was indicative of neuronal cell-specific expression. [0142] FIG.33B shows a bar plot of enhancer activity in either human induced pluripotent stem cell derived neurons (iPSC; solid line bars) or mouse primary neurons (MPN; dashed line bars). Activity was determined by measuring expression levels of hPGRN under control of an enhancer of each of SEQ ID NO: 1 – SEQ ID NO: 20, an RSV promoter, a human synapsin promoter (“hSyn”), or a scrambled promoter (“scrambled”) in neuronal cells (iPSC or MPN) using the dual cassette illustrated in FIG.32. Cells that were not transduced with virus (“no virus”) were included as a negative control. Progranulin expression was normalized to luciferase expression to account for differences in transduction efficiency. [0143] FIG.34 schematically illustrates an expression cassette for evaluating enhancer activity. The cassette includes an expression construct encoding a human progranulin (“hPGRN”) under control of an enhancer (e.g., any of SEQ ID NO: 1 – SEQ ID NO: 20) (“Enhancer”) and a minP variant core promoter of SEQ ID NO: 95 (“minP core promoter”) with a WPRE3 regulatory element and a polyA sequence. [0144] FIG.35A shows brain RNA levels of human progranulin in mice after injection with expression cassettes having a promoter comprising a CNS enhancer of SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, or SEQ ID NO: 13 paired with a minP variant core promoter of SEQ ID NO: 95, the RSV promoter (“RSV”), or the human synapsin promoter (“hSyn”). [0145] FIG.35B shows liver RNA levels of human progranulin in mice after injection with expression cassettes having a promoter comprising a CNS enhancer of SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, or SEQ ID NO: 13 paired with a -26- ^{Docket No. 421688-718021 (718WO1)} minP variant core promoter of SEQ ID NO: 95, the RSV promoter (“RSV”), or the human synapsin promoter (“hSyn”). [0146] FIG.35C shows expression of human progranulin in the cerebrospinal fluid (CSF) of mice after injection with expression cassettes having a promoter comprising a CNS enhancer of SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, SEQ ID NO: 13, or SEQ ID NO: 4 and SEQ ID NO: 15 (“SEQ ID NOs: 4 + 15”) paired with a minP variant core promoter of SEQ ID NO: 95, the RSV promoter (“RSV”), or the human synapsin promoter (“hSyn”). [0147] FIG.35D shows expression of human progranulin in the serum of mice after injection with expression cassettes having a promoter comprising a CNS enhancer of SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, or SEQ ID NO: 13 paired with a minP variant core promoter of SEQ ID NO: 95, the RSV promoter (“RSV”), or the human synapsin promoter (“hSyn”). [0148] FIG.36 shows a block diagram of a recombinant polynucleotide of SEQ ID NO: 312. The recombinant polynucleotide of SEQ ID NO: 312 includes, from 5’ to 3’, a 5’ inverted terminal repeat (“5’ ITR”) of SEQ ID NO: 307, a 5’ stuffer sequence (“5’ Stuffer”) of SEQ ID NO: 309, a CNS-enhancer (“CNS Enhancer”) of SEQ ID NO: 4, a minP variant core promoter (“minP Var”) of SEQ ID NO: 95, a 5’ untranslated region (“5’ UTR”) of SEQ ID NO: 310 (which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter (overlap not shown) and a Kozak sequence of SEQ ID NO: 354), a progranulin coding sequence (“GRN Coding Sequence”) of SEQ ID NO: 350, a HindIII restriction site, a WPRE3 post-transcriptional regulatory element (“WPRE3”) of SEQ ID NO: 288, a XbalI restriction site, a polyadenylation signal (“PolyA”) of SEQ ID NO: 299, a NotI restriction site, a transcriptional pause site (“Pause Site”) of SEQ ID NO: 311, a SalI restriction site, a PstI restriction site, and a 3’ inverted terminal repeat (“3’ ITR”) of SEQ ID NO: 308. [0149] FIG.37A shows a bar graph comparing transcriptional activity in H4 cells of enhancer/core promoter constructs comprising a HepG2-enhancer (SEQ ID NO: 362), an H4- specific enhancer (SEQ ID NO: 360), or an inactive enhancer (SEQ ID NO: 361) paired with a core promoter of SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, or SEQ ID NO: 107. The transcriptional activity was represented by GFP-reporter mean fluorescence intensity normalized to mCherry-reporter mean fluorescence intensity (“GFP gMFI / mCherry gMFI”) measured by flow cytometry from a dual reporter assay. -27- ^{Docket No. 421688-718021 (718WO1)} [0150] FIG.37B shows a bar graph comparing transcriptional activity in HepG2 cells of enhancer/core promoter constructs comprising a HepG2-enhancer (SEQ ID NO: 362), an H4- specific enhancer (SEQ ID NO: 360), or an inactive enhancer (SEQ ID NO: 361) paired with a core promoter of SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, or SEQ ID NO: 107. The transcriptional activity was represented by GFP-reporter mean fluorescence intensity nromalized to mCherry-reporter mean fluorescence intensity (“GFP gMFI / mCherry gMFI”) measured by flow cytometry from a dual reporter assay. [0151] FIG.38A shows a bar graph comparing fold change of transcriptional activity in H4 cells of enhancer/core promoter constructs comprising an H4-enhancer (SEQ ID NO: 360) compared to the activity of enhancer/core promoter constructs comprising an inactive enhancer (SEQ ID NO: 361), in which each enhancer was paired with a core promoter of SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, or SEQ ID NO: 107. The transcription activity of the active enhancer (H4-enhancer (SEQ ID NO: 360)) was divided by transcriptional activity of the inactive enhancer (SEQ ID NO: 361) to give the fold- change on the y-axis. [0152] FIG.38B shows a bar graph comparing fold change of transcriptional activity in HepG2 cells of enhancer/core promoter constructs comprising a HepG2-enhancer (SEQ ID NO: 362) compared to the activity of enhancer/core promoter constructs comprising an inactive enhancer (SEQ ID NO: 361), in which each enhancer was paired with a core promoter of SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, or SEQ ID NO: 107. The transcription activity of the active enhancer (HepG2-enhancer (SEQ ID NO: 362)) was divided by transcriptional activity of the inactive enhancer (SEQ ID NO: 361) to give the fold- change on the y-axis. [0153] FIG.39A shows a bar graph of human progranulin expression (“PGRN”) measured in serum of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). Progranulin expression is also compared to untreated control (“Untreated Control”). Progranulin expression in knockout mice (“PGRN KO”) was compared to wildtype c57 mice (“WT”). [0154] FIG.39B shows a bar graph of human progranulin expression (“PGRN”) measured in cerebrospinal fluid (CSF) of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). Progranulin expression is also compared to untreated control (“Untreated Control”). -28- ^{Docket No. 421688-718021 (718WO1)} Progranulin expression in knockout mice (“PGRN KO”) was compared to wildtype c57 mice (“WT”). [0155] FIG.40A shows a bar graph of human progranulin expression (“PGRN”) measured in serum of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). Progranulin expression is also compared to untreated control (“Untreated Control”). Progranulin expression in knockout mice (“PGRN KO”) was compared to wildtype c57 mice (“WT”). [0156] FIG.40B shows a bar graph of human progranulin expression (“PGRN”) measured in cerebrospinal fluid (CSF) of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). Progranulin expression is also compared to untreated control (“Untreated Control”). Progranulin expression in knockout mice (“PGRN KO”) was compared to wildtype c57 mice (“WT”). [0157] FIG.41A shows a bar graph of human progranulin expression (“PGRN”) measured in liver tissue of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). Progranulin expression is also compared to untreated control (“Untreated Control”). Progranulin expression in knockout mice (“PGRN KO”) was compared to wildtype c57 mice (“WT”). [0158] FIG.41B shows a bar graph of human progranulin expression (“PGRN”) measured in brain tissue of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). Progranulin expression is also compared to untreated control (“Untreated Control”). Progranulin expression in knockout mice (“PGRN KO”) was compared to wildtype c57 mice (“WT”). [0159] FIG.42A shows a bar graph of human progranulin expression (“PGRN”) measured in liver tissue of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). Progranulin expression is also compared to untreated control (“Untreated Control”). Progranulin expression in knockout mice (“PGRN KO”) was compared to wildtype c57 mice (“WT”). -29- ^{Docket No. 421688-718021 (718WO1)} [0160] FIG.42B shows a bar graph of human progranulin expression (“PGRN”) measured in brain tissue of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). Progranulin expression is also compared to untreated control (“Untreated Control”). Progranulin expression in knockout mice (“PGRN KO”) was compared to wildtype c57 mice (“WT”). [0161] FIG.43A shows a bar graph of AAV transduction (vg/dg) measured in liver tissue of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). AAV transduction (vg/dg) is also compared to untreated control (“Untreated Control”). AAV transduction (vg/dg) in knockout mice (“GRN KO”) was compared to wildtype c57 mice (“c57”). The transduction efficiency was measured by the quantification of the vector genome per diploid genome (vg/dg), in which the viral genomes were normalized against mouse transferrin receptor (mTFRC) for the calculating the vg/dg values (“Brain vg/dg (against mTRFC)”). [0162] FIG.43B shows a bar graph of AAV transduction (vg/dg) measured in brain tissue of male and female mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). AAV transduction (vg/dg) is also compared to untreated control (“Untreated Control”). AAV transduction (vg/dg) in knockout mice (“GRN KO”) was compared to wildtype c57 mice (“c57”). The transduction efficiency was measured by the quantification of the vector genome per diploid genome (vg/dg), in which the viral genomes were normalized against mouse transferrin receptor (mTFRC) for the calculating the vg/dg values (“Brain vg/dg (against mTRFC)”). [0163] FIG.44 shows a plot of the correlation between AAV transduction in the liver (“Liver vg/dg Quant”) and progranulin expression in the liver (“Liver Protein (pg/ml)/ug total protein”) of male and female progranulin knockout mice 8-weeks post IV delivery of AAV vectors produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). AAV transduction (vg/dg) is also compared to untreated control (“Untreated Control”). [0164] FIG.45 shows a plot of the correlation between AAV transduction in the brain (“Brain vg/dg Quant”) and progranulin expression in the brain (“Brain Protein (pg/ml)/ug total protein”) of male and female progranulin knockout mice 8-weeks post IV delivery of AAV vectors -30- ^{Docket No. 421688-718021 (718WO1)} produced by triple transient transfection using a plasmid of SEQ ID NO: 388, a plasmid of SEQ ID NO: 355, or a negative control plasmid (does not encode for progranulin, “Negative Control”). AAV transduction (vg/dg) is also compared to untreated control (“Untreated Control”). [0165] FIG.46 shows a plot of the abundance of AAV-delivered vectors comprising a payload under the transcriptional control of a either a control promoter, comprising a sequence of SEQ ID NO: 389 (“Control”), or a liver-specific promoter comprising the liver-enhancer of SEQ ID NO: 362 paired with the core promoter of SEQ ID NO: 95 (“Liver-Specific”) in heart and liver tissues of non-human primates. The abundance of the promoters was measured by the ratio of Control/Liver-Specific abundance as a log2(ratio) after normalizing RNA by corresponding DNA abundances in either heart tissue or liver tissue. DETAILED DESCRIPTION [0166] Described herein are polynucleotide compositions comprising a sequence encoding an enhancer for tissue type-specific or cell type-specific transcription of a payload. An enhancer of the present disclosure may be a central nervous system (CNS)-enhancer that enhances payload transcription in central nervous system tissues or cells. When included in a promoter along with a core promoter sequence, a CNS-enhancer of the present disclosure may promote CNS-specific transcription of a payload under transcriptional control of the promoter. A promoter comprising a CNS-enhancer of the present disclosure may have increased promoter strength, increased CNS specificity, smaller size, or combinations thereof, compared to a constitutive promoter or to other CNS promoters. The increased CNS specificity provided by the CNS-enhancers of the present disclosure may increase efficacy of a payload (e.g., a therapeutic payload) in CNS tissue while reducing side effects resulting from off-target expression of the payload in non-CNS tissues. The compact size of the CNS-enhancers described herein may facilitate incorporation into a vector (e.g., a plasmid or a viral vector) due to the limited capacity of the vector. [0167] An enhancer of the present disclosure may be a liver-enhancer that enhances payload transcription in liver tissues or cells. When included in a promoter along with a core promoter sequence, a liver-enhancer of the present disclosure may promote liver-specific transcription of a payload sequence under transcriptional control of the promoter. A promoter comprising a liver- enhancer of the present disclosure may have increased promoter strength, increased liver specificity, smaller size, or combinations thereof, compared to a constitutive promoter or to other liver promoters. The increased liver specificity provided by the liver-enhancers of the present disclosure may increase efficacy of a payload (e.g., a therapeutic payload) in liver tissue while reducing side effects resulting from off-target expression of the payload in non-liver tissues. The -31- ^{Docket No. 421688-718021 (718WO1)} compact size of the liver-enhancers described herein may facilitate incorporation into a vector (e.g., a plasmid or a viral vector) due to the limited capacity of the vector. [0168] An enhancer of the present disclosure may be part of a promoter to promote tissue type- specific or cell type-specific transcription of the payload. The promoter may include a CNS- enhancer and may promote CNS-specific payload transcription. The promoter may include a liver-enhancer and may promote liver-specific payload transcription. A promoter may comprise an enhancer and a core promoter and may regulate transcription of a corresponding payload. Described herein are polynucleotide compositions comprising a sequence encoding a promoter for tissue type-specific or cell type-specific transcription (e.g., CNS-specific transcription or liver-specific transcription) of the payload. Further described herein are polynucleotide compositions comprising the payload, such as a transgene, under transcriptional control of the promoter. The polynucleotide compositions may comprise a recombinant polynucleotide. The polynucleotide compositions of the present disclosure may encode for tissue type-specific or cell type-specific transcription of the payload. In some embodiments, the level of transcription of the payload may depend on a cell type (e.g., neuron, renal cell, hepatocyte, podocyte, retinal cell, epithelial cell, muscle cell, erythrocyte, platelet, bone marrow cell, endothelial cell, epidermal cell, lymphocyte, glial cell, interstitial cell, adipocyte, or fibroblast), tissue type (e.g., nervous tissue, kidney tissue, eye tissue, muscle tissue, blood, skin, fat, bone, cancerous tissue, thymus tissue, gastrocnemius tissue (e.g., stomach, intestine), spleen tissue, placenta tissue, pancreatic tissue, lung tissue, liver tissue, cardiac tissue, or brain tissue (e.g., cerebrum, cerebellum, adrenal)), or a combination thereof. [0169] The enhancer may be a CNS-enhancer and may be selected for enhanced transcription in CNS tissue or CNS cells, reduced transcription in non-CNS tissue or non-CNS cells, or both. In some embodiments, the enhancer may be selected or engineered to tune the level of payload transcription in the CNS (e.g., to a therapeutic level, such as about the same level as a wildtype version of a transgene in the CNS). In some embodiments, the enhancer may be selected or engineered to tune the level of payload transcription in non-CNS tissue (e.g., to below a level that produces off-target effects). A promoter comprising an enhancer may be selected for enhanced transcription in CNS tissue or cells, reduced transcription in non-CNS tissue or non- CNS cells, or both. In some embodiments, the promoter may be selected or engineered to tune the level of payload transcription in the CNS (e.g., to a therapeutic level, such as about the same level as a wildtype version of a transgene in the CNS). In some embodiments, the promoter may be selected or engineered to tune the level of payload transcription in non-CNS tissue (e.g., to below a level that produces off-target effects). Tuning a transcription level may comprise -32- ^{Docket No. 421688-718021 (718WO1)} adjusting transcription to a desired level. The transcription level of the payload may control the expression level of the protein encoded by the payload. For example, a high level of transcription of a transgene may lead to a high level of expression of the protein encoded by the transgene. [0170] The enhancer may be a liver-enhancer and may be selected for enhanced transcription in liver tissue or liver cells, reduced transcription in non-liver tissue or non-liver cells, or both. In some embodiments, the enhancer may be selected or engineered to tune the level of payload transcription in the liver (e.g., to a therapeutic level, such as about the same level as a wildtype version of a transgene in the liver). In some embodiments, the enhancer may be selected or engineered to tune the level of payload transcription in non-liver tissue (e.g., to below a level that produces off-target effects). A promoter may be selected for enhanced transcription in liver tissue or liver cells, reduced transcription in non-liver tissue or non-liver cells, or both. In some embodiments, the promoter may be selected or engineered to tune the level of payload transcription in the liver (e.g., to a therapeutic level, such as about the same level as a wildtype version of a transgene in the liver). In some embodiments, the promoter may be selected or engineered to tune the level of payload transcription in non-liver tissue (e.g., to below a level that produces off-target effects). Tuning a transcription level may comprise adjusting transcription to a desired level. The transcription level of the payload may control the expression level of the protein encoded by the payload. For example, a high level of transcription of a transgene may lead to a high level of expression of the protein encoded by the transgene. [0171] Also described herein are methods of delivering a polynucleotide composition of the present disclosure to a subject. In some embodiments, the polynucleotide composition may be encoded in a viral vector capable of delivering the polynucleotide to a cell of the subject. The viral vector may further comprise a viral capsid encapsidating the polynucleotide and facilitating delivery of the polynucleotide into the cell. A method of delivering a polynucleotide composition to a subject may comprise administering a viral vector comprising the polynucleotide to the subject. Upon delivery of the polynucleotide to the subject, a payload encoded by the polynucleotide may be transcribed in a cell of the subject in a cell type or tissue- type-dependent manner. [0172] Further described herein are methods of treating a disease or condition by delivering a polynucleotide composition of the present disclosure to a subject and expressing a protein encoded by the polynucleotide in the subject in a cell type- or tissue type-dependent manner. The polynucleotide composition may be delivered to the subject as part of a viral vector. The subject may have a disease or condition, for example a disease or condition caused by mutation or -33- ^{Docket No. 421688-718021 (718WO1)} altered expression of a protein. In some embodiments, the polynucleotide composition may comprise a transgene encoding a wild type copy of the protein having the mutation or altered expression. The transgene may be selectively transcribed in a target cell type or target tissue type of the subject upon delivery of the polynucleotide composition to the subject. In some embodiments, a protein encoded by the transgene is expressed in the subject at a level dependent on the level of transcription of the transgene. Transcription of the transgene, expression of the protein encoded by the transgene, or both, in a cell type or tissue tyle-dependent manner may treat the disease or condition in the subject. [0173] Also described herein are tissue-specific enhancer/promoter (e.g., enhancer/core promoter) libraries, methods of generating tissue-specific enhancer/promoter (e.g., enhancer/core promoter) libraries, and methods of screening tissue-specific enhancer/promoter (e.g., enhancer/core promoter) libraries to identify enhancers that promote tissue type- or cell type-specific transcription. A tissue-specific enhancer/promoter (e.g., enhancer/core promoter) library may comprise candidate enhancers expected to promote tissue type- or cell-type-specific transcription of nearby sequences along with reference sequences for cross-comparison. The libraries may be screened using high-throughput screening to assess transcription in a cellular model of the cell or tissue of interest (e.g., cultured neurons, cultured hepatocytes, or cancer cell lines) or in animal models (e.g., mice, rats, dogs, non-human primates). [0174] Also described herein are recombinant polynucleotides for expressing a payload (e.g., a transgene). A recombinant polynucleotide of the present disclosure can be used to treat a disease or disorder caused by a mutation, deletion, or altered expression of a gene. For example, a recombinant polynucleotide can be used to treat a disease or disorder caused by a mutation, deletion, or altered expression of a gene by expressing a wild type copy of the gene encoded by the recombinant polynucleotide. Various sequence elements, such as promoters, introns, post- transcriptional regulatory elements, transcriptional pause sites, or polyadenylation signals can affect transcriptional levels of a payload encoded by the recombinant polynucleotide. Described herein are sequence elements and recombinant polynucleotides comprising sequence elements for expression of a payload (e.g., a progranulin payload). Variation of the sequence elements included in a recombinant polynucleotide can be used to tune expression levels, locations (e.g., cells, tissues, or secreted fluids), or both of a payload encoded by the recombinant polynucleotide. [0175] A recombinant polynucleotide can comprise a promoter of a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) and a coding sequence under transcriptional control of the promoter. For example, the coding sequence encodes a progranulin protein and the -34- ^{Docket No. 421688-718021 (718WO1)} promoter comprises a CNS-enhancer and a core promoter. In some embodiments, the recombinant polynucleotide includes additional sequence elements that enhance transcription of the payload. Examples of additional sequence elements that can be included in a recombinant polynucleotide are an intron, a polyadenylation signal (polyA signal) encoding a signaling addition of a polyadenylation tail (polyA tail), a post-transcriptional regulatory element, a transcriptional pause site, a neuron-restrictive silencer element (NRSE), a CCCTC-binding factor (CTCF) sequence, or any combination thereof. For example, a recombinant polynucleotide includes a tissue-specific enhancer/promoter (e.g., enhancer/core promoter), a coding sequence encoding progranulin, a post-transcriptional regulatory element, a polyadenylation signal, and a transcriptional pause site. A coding sequence encoding the payload can be operably linked to a promoter comprising a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) sequence, such that the promoter regulates expression of the payload. The payload can be a progranulin. In some embodiments, a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) promotes different levels of payload expression in different cell types, tissue types, organs, or body regions. For example, a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) promotes different levels of payload expression in a cerebrospinal fluid compared to in a serum of a subject administered the recombinant polynucleotide. [0176] The recombinant polynucleotide can be used to treat a disease or disorder. In some embodiments, the recombinant polynucleotide can be delivered via viral vector to treat a disease or disorder to a subject in need thereof. For example, the recombinant polynucleotide comprises a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) sequence operably linked to a GRN sequence for the expression of progranulin and is used to treat frontotemporal dementia (FTD). The progranulin can be expressed in a cerebrospinal fluid of a subject to treat the frontotemporal dementia in the subject. The cerebrospinal fluid is secreted by a cell of tissue expressing the progranulin. In some embodiments, the GRN sequence comprises no introns. In some embodiments, the GRN sequence comprises all native GRN introns. In some embodiments, the GRN sequence comprises only introns. In some embodiments, the GRN sequence comprises one or more introns (e.g., one or more native GRN introns). In some embodiments, the recombinant polynucleotide comprises an intron. The intron can a GRN intron, such as intron 9. Intron 9 can be located in the GRN sequence. The intron can be an SV40 intron. The SV40 intron can be located downstream of the promoter sequence and upstream of the translational start site of the GRN sequence. In some embodiments, the recombinant polynucleotide comprises a NRSE. In some embodiments, the recombinant polynucleotide comprises a CTCF sequence. In some embodiments, the recombinant polynucleotide further comprises sequence element, such as a WPRE or variant thereof. In some embodiments, the recombinant -35- ^{Docket No. 421688-718021 (718WO1)} polynucleotide further comprises a polyadenylation signal sequence, such as a rabbit beta globulin polyA sequence. Promoters [0177] A polynucleotide (e.g., an RNA or a DNA polynucleotide) may comprise a promoter sequence to regulate or enhance transcription of a payload, such as a transgene. In some embodiments, the promoter may comprise an enhancer and a core promoter sequence that functions as a site for preinitiation complex formation, or combinations thereof. In some embodiments, the enhancer and core promoter sequence may together be referred to as “enhancer/promoter.” In some embodiments, the enhancer may comprise a transcription factor (TF) binding sequence that binds one or more transcription factors. In some embodiments, the core promoter may comprise a minimal synthetic promoter or a natural promoter. The elements within the promoter (e.g., the enhancer or the core promoter) may be selected or engineered to alter transcription rates of a downstream transgene. For example, the promoter may be selected to promote high levels of transcription in target cell or tissue type (e.g., CNS tissue or neurons or liver tissue or cells) and low levels or no transcription in non-target cell types (e.g., non-CNS tissue or non-neuronal cells such a hepatocytes or non-liver cells). In some embodiments, the target tissue may be CNS tissue (e.g., cerebrum, cerebellum, adrenal). In some embodiments, the target cells may be CNS cells (e.g., neurons or glial cells). In some embodiments, the non-target tissue may be kidney tissue, eye tissue, muscle tissue, blood, skin, fat, bone, thymus tissue, gastrointestinal tissue (e.g., stomach, intestine), spleen tissue, placenta tissue, pancreatic tissue, lung tissue, liver tissue, or cardiac tissue. In some embodiments, the target tissue may be CNS tissue (e.g., cerebrum, cerebellum, adrenal) and the non-target tissue may be kidney tissue, eye tissue, muscle tissue, blood, skin, fat, bone, thymus tissue, gastrointestinal tissue (e.g., stomach, intestine), spleen tissue, placenta tissue, pancreatic tissue, lung tissue, liver tissue, or cardiac tissue, or any combination thereof. In some embodiments, the non-target cell type may be renal cell, hepatocyte, podocyte, retinal cell, epithelial cell, muscle cell, erythrocyte, platelet, bone marrow cell, endothelial cell, epidermal cell, lymphocyte, interstitial cell, adipocyte, or fibroblast. In some embodiments, the target cells may be CNS cells (e.g., neurons or glial cells) and the non-target cell type may be renal cell, hepatocyte, podocyte, retinal cell, epithelial cell, muscle cell, erythrocyte, platelet, bone marrow cell, endothelial cell, epidermal cell, lymphocyte, interstitial cell, adipocyte, or fibroblast, or any combination therof. In some embodiments, the target tissue may be liver tissue. In some embodiments, the target cell type may be liver cells (e.g., hepatocytes, hepatic stellate cells, Kupffer cells, or liver sinusoidal endothelial cells). In some embodiments, the non-target tissue may be nervous tissue, kidney tissue, eye tissue, -36- ^{Docket No. 421688-718021 (718WO1)} muscle tissue, blood, skin, fat, bone, thymus tissue, gastrointestinal tissue (e.g., stomach, intestine), spleen tissue, placenta tissue, pancreatic tissue, lung tissue, cardiac tissue, or brain tissue (e.g., cerebrum, cerebellum, adrenal). In some embodiments, the target tissue may be liver tissue and the non-target tissue may be nervous tissue, kidney tissue, eye tissue, muscle tissue, blood, skin, fat, bone, thymus tissue, gastrointestinal tissue (e.g., stomach, intestine), spleen tissue, placenta tissue, pancreatic tissue, lung tissue, cardiac tissue, or brain tissue (e.g., cerebrum, cerebellum, adrenal), or any combination thereof. In some embodiments, the non- target cell type may be neuron, renal cell, podocyte, retinal cell, epithelial cell, muscle cell, erythrocyte, platelet, bone marrow cell, endothelial cell, epidermal cell, lymphocyte, glial cell, interstitial cell, adipocyte, or fibroblast. In some embodiments, the target cell type may be liver cells (e.g., hepatocytes, hepatic stellate cells, Kupffer cells, or liver sinusoidal endothelial cells) and the non-target cell type may be neuron, renal cell, podocyte, retinal cell, epithelial cell, muscle cell, erythrocyte, platelet, bone marrow cell, endothelial cell, epidermal cell, lymphocyte, glial cell, interstitial cell, adipocyte, or fibroblast, or any combination thereof. [0178] In some embodiments, a promoter may promote tissue-specific transcription if it promotes transcription of a transgene in a target tissue type (e.g., CNS tissue or liver tissue) at a level that is at least about 0.1-fold, at least about 0.25-fold, at least about 0.5-fold, at least about 0.75-fold, at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3- fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold a transcription level of the transgene in a non-target tissue (e.g., non-CNS tissue or non-liver tissue). [0179] In some embodiments, a promoter may promote cell type-specific transcription if it promotes transcription of a transgene in a target cell type (e.g., CNS cells or liver cells) at a level that is at least about 0.1-fold, at least about 0.25-fold, at least about 0.5-fold, at least about 0.75- fold, at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30- fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold a transcription level of the transgene in a non-target cell type (e.g., non-CNS cells or non-liver cells). [0180] In some embodiments, a promoter may promote a desired level of transcription if it promotes transcription of a transgene in a target tissue (e.g., CNS tissue or liver tissue) at a level -37- ^{Docket No. 421688-718021 (718WO1)} that is at least about -0.75 fold, at least about -0.5 fold, at least about -0.25-fold, at least about - 0.1-fold, at least about 0-fold, at least about 0.1-fold, at least about 0.25-fold, at least about 0.5- fold, at least about 0.75-fold, at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100- fold, at least about 150-fold, or at least about 200-fold a transcription level of a wildtype version of the transgene in a target tissue (e.g., CNS tissue or liver tissue). [0181] In some embodiments, a promoter may promote a desired level of transcription if it promotes transcription of a transgene in a target cell type (e.g., CNS cells or liver cells) at a level that is at least about -0.75 fold, at least about -0.5 fold, at least about -0.25-fold, at least about - 0.1-fold, at least about 0-fold, at least about 0.1-fold, at least about 0.25-fold, at least about 0.5- fold, at least about 0.75-fold, at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100- fold, at least about 150-fold, or at least about 200-fold a transcription level of a wildtype version of the transgene in a target cell type (e.g., CNS cells or liver cells). [0182] An engineered polynucleotide of the present disclosure may comprise a payload sequence (e.g., a sequence encoding a protein) operably linked to a promoter (e.g., comprising a core promoter and an enhancer). An engineered polynucleotide can comprise a payload sequence (e.g., a sequence encoding a protein) under transcriptional control of a promoter. An engineered polynucleotide comprising a promoter can further comprise one or more additional elements (e.g., a post-transcriptional regulatory element, a polyadenylation signal, a transcriptional pause site, a neuron-restrictive silencer element, a CCCTC-binding factor sequence, a 5’ untranslated region, a 3’ untranslated region, a 5’ stuffer sequence, or combinations thereof). In some embodiments, the payload sequence encodes progranulin. In some embodiments, the engineered polynucleotide comprises a 5’ stuffer sequence, a promoter as disclosed herein (e.g., a CNS- enhancer paired with a core promoter, e.g., SEQ ID NO: 4 paired with SEQ ID NO: 95), a 5’UTR, a payload sequence (e.g., a sequence encoding progranulin), a WPRE3 sequence, a polyadenylation signal (e.g., a rabbit beta globin sequence), and a pause site. In some embodiments, the engineered polynucleotide comprises a 5’ITR sequence, a 5’ stuffer sequence, a promoter as disclosed herein (e.g., a CNS-enhancer paired with a core promoter, e.g., SEQ ID NO: 4 paired with SEQ ID NO: 95), a 5’UTR, a payload sequence (e.g., a sequence encoding -38- ^{Docket No. 421688-718021 (718WO1)} progranulin), a WPRE3 sequence, a polyadenylation signal (e.g., a rabbit beta globin sequence), a pause site, and a 3’ITR sequence (e.g., a sequence of SEQ ID NO: 312). Enhancers [0183] The promoter of a polynucleotide may comprise an enhancer. An enhancer is any sequence that works to enhance the rate of transcription. An enhancer paired with a core promoter as described herein may originally have been located upstream or downstream of and/or in the same or different orientation as a gene in a cell type of interest. An enhancer paired with a core promoter as described herein may originally have been located in an exon or intron of and/or in the same or different orientation as a gene in a cell type of interest. The enhancer may recruit proteins to the polynucleotide that enhance, repress, or alter transcription of a downstream sequence (e.g., a transgene sequence encoded by the polynucleotide). In some embodiments, an enhancer may bind transcription factors that promote transcription (e.g., by recruiting an RNA polymerase) of nearby coding sequences. [0184] The enhancer may comprise a transcription factor binding sequence that binds one or more transcription factors. The enhancer may comprise a portion of a transcription factor binding sequence that binds one or more transcription factors. The enhancer may comprise a motif of a transcription factor binding sequence that binds one or more transcription factors. The transcription factor binding sequence, the portion of the transcription factor binding sequence, or the motif of the transcription factor binding sequence may recruit one or more transcription factors to the polynucleotide that enhance, repress, or alter transcription of a downstream sequence (e.g., a transgene sequence encoded by the polynucleotide). The one or more transcription factors may be CNS-specific transcription factors. The one or more transcription factors may be liver-specific transcription factors. CNS-Enhancers [0185] The enhancers may be tissue specific enhancers (e.g., CNS-enhancers). A tissue specific enhancer may result in enhanced, repressed, or altered transcription of a downstream sequence (e.g., a transgene sequence encoded by the polynucleotide) in a specific cell type of a tissue or tissue type (e.g., CNS cells or CNS tissue). The tissue specific enhancers and core promoters described herein may be appended or operably linked to a payload (e.g., a transgene encoding a therapeutic protein) to promote tissue-specific transcription of the payload. In some embodiments, enhancers may be combined or used in combination with other enhancers to tune transcriptional levels of the payload. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more enhancers may be combined to tune transcriptional levels of the payload. The combined 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more enhancers may all be the same enhancer, different enhancers, or any -39- ^{Docket No. 421688-718021 (718WO1)} combination thereof. In some embodiments, an enhancer (e.g., an enhancer of any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may be duplicated or repeated 2, 3, 4, or more times. In some embodiments, a first enhancer (e.g., any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may be combined with one or more additional enhancers (e.g., one or more of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385). In some embodiments, an enhancer (e.g., an enhancer of any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may be duplicated or repeated 2, 3, 4, or more times and may be combined with one or more additional enhancers (e.g., one or more of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385), wherein the one or more additional enhancers (e.g., one or more of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may be duplicated or repeated 2, 3, 4, or more times. [0186] In some embodiments, a tissue-specific enhancer may be a CNS-enhancer. Examples of CNS-enhancers are provided in TABLE 1. TABLE 1 – CNS-Enhancers SEQ ID _NO: ^Sequence SEQ ID CCCCTATAGTAGGCCAGCCTATGAACGCAACCGGCAAATTTCGACCAATCCGAGTCTAGCT NO: 1 CTTCTGGATTCCCAGCATGCAGCGCAGACCCTGATCCAATTGCTGTAAAGACGCATCCTTAG AGAGGCTCTCGGGAGTCCGAGAGAGCACTGCATTCTGGGATTTGTAG SEQ ID AGGATGGTAGAGGAAGTCCCGCCCTGACGTTGGTGAGGACCAACGGAAACGCCTATTTCCT NO: 2 GGGTTTTCATTGGCCCAGAGCCGCCAAGTTTCCTGGGTAATGTAGTTCCCACGGCACCAACA CTAGTAAGCGGCGTCTCGCTTCACCTCCAGGTTAAAAGCCCAGAGAA SEQ ID ACCCAGTCTCAGTAGCTTGGTAGTTACCATGGCTCCCAGTGCTGTGCGTCTGACGTCATTCT NO: 3 GCGGCGCTGGCTGATGGCGCAATCAGTTGCGGCGTCCTGTGAGCGCGGGGATGCTGGGAGG AGGGTGAAATTTAGCCATCGGTGTGTGGCAGGGTCATGAAAAAGCGG SEQ ID AGCTCCCCAAACCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAG NO: 4 ATGATGCTCCAGTTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCA GAGCAGCCAGTGAGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCC SEQ ID GCCTCCTCCTCCGCGATTCAGGTTTAACCCCTTCGGGCTCCAGAGCGGCTGCGCTGGGGTGG GGGCGGAGTCTGTCTCCGCGGCAACAAGGCAGAAAGAATCCCGGGGGACCCAGGTCGCCA NO: 5 TAGCAACGGGAGCGCTGGGGCGCCCCCGCCCTACGGGAGCTGTTTCCC SEQ ID ACGCCCGTTGCGAGGACACCCTGGGCCTGTGCCCTCCTACTAGCACCGCCCTCCTCGTCTGC NO: 6 AGTAGCCAATCAACACGAGGCTTGTAGGCTGCCGTTCCTCGATTGGCTACGGCTCTAGCTCC GCCCGCCGCACTTGGCGACGGTGTCCGGCGGGGAGGCGGCGGCTTC SEQ ID AGATGGTAGGACTGTTGATACGCTCTGATTGGATGAAATGGGGAGCCCCGCCCCAGGGTAG NO: 7 GCGCTCTTTGGTGCAGTATACGAAACGAGCGAAGGCGAGAACGCATGCGCAAATACGCTTT CAGGCACCGCCCAGAGGCGGGGCCCCCTTATGGAGCGACCGCTGTGTG -40- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence SEQ ID AGCTTGAGGCTGGTTGGAAGCCAGGAAGAGTCCCAGCCCCTCCCACGTCAGCATCCCTGTG NO: 8 GGCGCACAGCCCGGCGGGCGGCGTGTGGCCTGCCGGGAGATGTAGTCCGTAGCGCAGTCCC GCGCCTGCGCCCTGGGCAGTTGCCGGTGAGCTTGGGAGAACCGTGGGC SEQ ID AGCAGCGTGGGAACTACATTACCCAGAAGACACTGCGGGCGACACAGGCAGCAACGTGAG NO: 9 AACTACATTACCCAGAAGACACTGCGGGGGCAGGGCAGCGAGTGTAGCCATTGGTCTAGCA GAGAGACGACTAATGAGGTCTCAATTGTGTGGGCGGGACTTCTGGCGGC SEQ ID GCCGCCGCGCTCCCCCCGCCCGACCGCCGCTCAGCTGGCGCGAGACTCCCGCTTCCGGGTTC NO: 10 TCAGAGGGCGGGGCCACGTCGCGAGGAAGGGGCGGTGCTGCGTGGCCCCGGCGGTCGCCA CGGCGACGGGCGCGGGGGGAGGCTCCGTGGGATGCTTGGCTGCGGCTG SEQ ID GCCTCGCGCCTGATTGACAATTCTCAGGAACCCGCCCACGACTTTGATTGGGTAGCCCTCCA NO: 11 GGTCCCGCCTCCTGGGCACTGAGTGACAGAAGAAGCGATCTCACAGTGCTGAGTGCAGCCG GATGAACAGGTTCCAGACCCGGCCCCTGGCAGGGCGGGCTTCCTCCC SEQ ID ACTTCTTTTCTCAGCCCTCGTCCACTGTTCTTTTTTAACCAATCAGAAACGTTTTTCAAACGT NO: 12 TTGCCCTCCCCGCTAAGTGCGCAGGCTCCTGGAAAGTTGTCTTCACTTCCGGGCCGCGGTCT AGGGCGGCTACGTGTGTTGCCATAGCGACCATTTTGCATTAACTG SEQ ID ATCGGAACCTATCCTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACG NO: 13 AGCGCGAGCGGAAAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTT GCGTCCCGGGTGCGTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCC SEQ ID GGGAGGGGATTGGCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGG NO: 14 GCGGGGCCAAGGCGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCA CCCGGTACCATGGCAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGA SEQ ID ATTTCCTCTTCTGTCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGAC NO: 15 CTGGTAGTGGGTGGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCA ACTTGGTTCCCTAGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGG SEQ ID ATTGGCTGGTCCTGGCAGTCGTCGGTCTCCGTGGCAACCGCCTCCTGTCTCCATGGCAACCA NO: 16 GGGATGGAGCCGACGAGAGCGCACCAGGGAAGGCGACCCGGATGGGTCGGTCTCCAGGTC TCTAGGCAACTCGGTGATCTGTCCTATCATCTCCCCTCCACCCCCACA SEQ ID CGCCGGTGTCTAACAGGATCCGGACCTAGCTCATATTGCTGCCGCAAAACGCAAGGCTAGC NO: 17 TTCCGCCAGTACTGCCGCAACACCTTCTTATTTCACGACGTATGGTCGTAAAGCAATAAAGA TCCAGGCTCGGGAAAATGACGGAGAGGTGGAACTATAGAGAATAAAT SEQ ID CAGCAGCTGCACGATTGTTATGTATTTTAAATAAAGCATTTAAAGCCACTCAGAATGTAGCA NO: 18 ACAATCACCATGGATACTCATCACTGAAATCCTTTGTTGCCGTGGCAACAGTCCACCCTTCC CCGCCTTCCCCCACCACCCATCTTGCCTGTTTACCCTGAAACTGAC SEQ ID TTTGATGGTGGGTTGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCC NO: 19 ACTCCAGCCCGGACAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAG TCACTATGGCAACCAGTGTCCCCCGTTCCCTTGGTTACCATGGGGAT SEQ ID TGATCTGACCCCCTCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATC NO: 20 CCTTACCAATTTGCTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGC TACCCAGTAACCATGGTAACGCCCTGGCAGTCACAGTTGAGCAATT SEQ ID GGCCGCAGCGCGCCCCCGGCCTCCCAGTCGCGCGCCAACCCGGGAGCGCGCGCGCCGGCGC NO: 21 ACCAGCTCCATCAGCTAGAGGAGCCCGTCTCCCGGGAAACACCAATCAGACGCCCGCTTTC AGGCGAGGGCCGCGAGCCGCAGCAGCTGCAGGAGGACTCGGGCAGTTG SEQ ID TTTGTTTTGGGGGTCCCCTTGCCCCCCTCCCCCGTCTCTCTCGCGCTGTCTCCGGGCGACAGG NO: 22 GCTCGTGACAGAGGCGGCCACGGCAGCAGCGGTCGCCTAGCAACGGCGGCGGGGCCCGGG CAACGGCGGCAGCGGCGGGAGCGGCGGCGGAGGGAGCCGTTCCCGCG SEQ ID ACATTTTGTTTCTGTGGTAACCAAAATCAGCTGATTAGTTGGCATGGCAACAGAAAAGATGT NO: 23 AATCCCAGCAGACACACTCTAATCAATGCCCCCAGTACAGATGGTCTCCGGAGGATCAACA AGAAAGAGGCTGGCAGGCATTCAGCCGATCACGTGCTAGCTTGAGAC -41- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence SEQ ID GCAGTGACACCCCTTCCGCCAAATTTGTTTCTCTTTCTTTCAGCGCCTGCGCGCTGTCACGTT NO: 24 ACGGCGGAACTAATCCAGCGACGCCTGCGCTTTGACGCATTTGGTGCCGTGGAAGGGAAAA AGGGGGACTGCAGTATGCGTCACACCCGGAAGCGGCGAGCCGGAAG SEQ ID TCATCCAGGGTCTCTCCCCCTCCGCTGCTGCCGCCGCCGCCGCCGCCGCTGCCGTTGCGCTC NO: 25 CAGGTCTGCGAACAGCGAGCTGGGCATCGCTCGGCCGTGCGCGCCGCGCCCCCGCCGGCCC TCGGCTCGGCGGCGAGAAGCTGCGGCCACAAAGGCAGCCGGGAAGCG SEQ ID ACTCCTGCGGACTACACATCCCGGCGGCCCATGCGGCCCCGTCACGTGATGCAAGGATCGC NO: 26 CGGCCTTTCCGCCAGAGGGCGGCACAGAACTACAACTCCCAGCAAGCTCCCAAGGCGGCCC TCCGCGCAATGCCGCTACCGGAAGTGCGGGTCGCGCTTCCGGCGGCGT SEQ ID TACCACGGCCAAGTACGAAGCCTTCGAGATAGCGTTCTTCTTACCCTACGTAAACACGCAGT NO: 27 TTCCCGAGCTCGACAATCGGCTAGCCACTCCTGATAGCGTTCGGCGCTCGCCTCTCGGCCCT TGCTCCTGCGTACTACGGCTTCTTCCAGTCACCTCGGCCCGGATCG SEQ ID GGCATAAGGGACCTTTTCTATTTGCAGAGCCTGAAGAAGCCGGTTGCCAAGGTGACAGGAG NO: 28 CAGGAACAGCAGGGAGCTTGCCATGGGGGAGGGGCTTTGCCCCCAAACAGCTGTCAGTGG GAGCAGTCCCAGCTGGGACTGGAGGGTCTGCCTGCTCTGGGAGGAAACA SEQ ID GCACGAAAAAGAAATTAAACCTAACTACCGTTCCCAGAGGGCGCCGCTCTGCAAATTACCC NO: 29 AATCAGCTCTAAGTACAAAGCATCGCGAGTCTTTAGTGCTCTTTGGCGCTATAAGCCCGTGG GAACGAGCATTGGAGACCCTTTTCACAAGATGGCGCCGAAAGCGAAG SEQ ID GGAGGAGGGACTTTGGCTAAAAATAGCTATGGCGTGTGGTTTGGATCAACCCCTAGTGGTA NO: 30 CCCAGGACTGGGGAGGGGAGGGGGATGCTCTGGAGCTGTCGCCAGACTGGTTGCCGTGGA AACAAGAGAGGAGCAGGGGAGCCTGGGAAGTAGGGATGACACAGATAGC SEQ ID CTCCTGCTGCAGCAGCAGAAGAGCCTGCAATTACAGCCTCAGGCACGCGCGTCACCACCAG NO: 31 TTCAGCGCAGCCAGGCGGGCTGTTGCCATGGGAACCATCCCTTGAATGGATGGATGCTGAG CTGTCCTGCGGCGGTTTCCATGGAGAAGGTCCTGATGTTCTCCAGTAA SEQ ID GCGAGTCATGGGACCGAACTGGGCGGTGTCGCTGTCCGTGGCCATGGTGCTGAACTCTGGG NO: 32 CGTGGCCAGAGAGATTTCCTTTACATGACAGCTTCCGGTAGGGCGGGGTCGGGGTCGCGTT CCGAAAAGTGGATCCACCTGCCACCTGGTGGCAGATGAGGAAAATGCT SEQ ID GAAGCTACACTGCCCTTCCCCCTCCATTTCCACTTTCCGTGCTCCCTTCCTCCCTTGGGAAGA NO: 33 TGCACGCTTGTTCCATTTGCACGCAGCACCAGCGTTGCCATGGAAACTCGCCTCCTTTTCTTC CCCCTCCCCAGTTACCAAGCTCAGCTTCTGGACTCAGTGCCAAG SEQ ID CCTCTCAGCCCCGCCTCGATTTTTAGCTTTATAGGAATGCTGTTGCTTTAAATCCGAAATCCC NO: 34 GTGCCGGTATCAACTCTCGCGATCTCCGAGGCCGCATACATATTACCCACAATTCCCTTTCC TTTCTCTCTCCTCCCGCCGCCCAAGATGGTGAGTGAGCTGTAGTT SEQ ID TGTTTCCTCCCAGAGCAGGCAGACCCTCCAGTCCCAGCTGGGACTGCTCCCACTGACAGCTG NO: 35 TTTGGGGGCAAAGCCCCTCCCCCATGGCAAGCTCCCTGCTGTTCCTGCTCCTGTCACCTTGG CAACCGGCTTCTTCAGGCTCTGCAAATAGAAAAGGTCCCTTATGCC SEQ ID CTTGGCACTGAGTCCAGAAGCTGAGCTTGGTAACTGGGGAGGGGGAAGAAAAGGAGGCGA NO: 36 GTTTCCATGGCAACGCTGGTGCTGCGTGCAAATGGAACAAGCGTGCATCTTCCCAAGGGAG GAAGGGAGCACGGAAAGTGGAAATGGAGGGGGAAGGGCAGTGTAGCTTC SEQ ID CCAGGGGTGATCTGGGCATCTGTTGCAGCAGAAGGCGCTTGTGTGGGGCTAATTTTTCTTTT NO: 37 GGTGGGGGGGACAAGCTGTTGGCTTGTTTGCTATTTCAACTTCGTTTATAATTAACTTAAAA AAAACCCCACCATTCAGCCTAGTCAACAACAAACAAAGAAAAAGCA SEQ ID AAGCTCTCCTCACCTGGAGCGGAAAATGGGACACACTCACCACACTCACACCCTCCCTGTC NO: 38 ATCCCCCACCCCATGGAAAGCCAAAGGAGGGCTATCACCATGGCAACTGCAGGCTACACGA GCTGCTGCATCACTGGTCCCTGGGGAAGGGGAACTGCCATCTGGGCAG SEQ ID CAGGGAGCTGACTTGAATATTCACGGTGCGTTTCCATGCATCTGTTCTAATAATGGAGACTC NO: 39 ATTTGCATTTAGAAAAAATGATTTGCATATAGACGATTAATGTAATAAGGTATCCAAAAAC AATTTTCCCCTTTGAATAAGCTGCCTTGTAATTTTGTTCACTTAATT -42- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence SEQ ID TGGCAGAGAAAACATGGGACCAGAATGTGTGTTATCTATGTGTGGCCAAATAAGACCCCGT NO: 40 GAATATTAAGTGCCCAAATATTTTGAGACTCATATATTGAATCACGTGTATATTTGGTATAT CATAAATATTTAGTACACAGGTGCTTCATAAAGATTAAATATCTCTT SEQ ID CTACAAATCCCAGAATGCAGTGCTCTCTCGGACTCCCGAGAGCCTCTCTAAGGATGCGTCTT NO: 41 TACAGCAATTGGATCAGGGTCTGCGCTGCATGCTGGGAATCCAGAAGAGCTAGACTCGGAT TGGTCGAAATTTGCCGGTTGCGTTCATAGGCTGGCCTACTATAGGGG SEQ ID TTCTCTGGGCTTTTAACCTGGAGGTGAAGCGAGACGCCGCTTACTAGTGTTGGTGCCGTGGG NO: 42 AACTACATTACCCAGGAAACTTGGCGGCTCTGGGCCAATGAAAACCCAGGAAATAGGCGTT TCCGTTGGTCCTCACCAACGTCAGGGCGGGACTTCCTCTACCATCCT SEQ ID CCGCTTTTTCATGACCCTGCCACACACCGATGGCTAAATTTCACCCTCCTCCCAGCATCCCC NO: 43 GCGCTCACAGGACGCCGCAACTGATTGCGCCATCAGCCAGCGCCGCAGAATGACGTCAGAC GCACAGCACTGGGAGCCATGGTAACTACCAAGCTACTGAGACTGGGT SEQ ID GGGAGTTGCGTCTTCTCCCTGCCCTGCCGAGCTGCTCACTGGCTGCTCTGGAGGCTGTGCTT NO: 44 TGCGGTCTCCATGGAAACCATTAGTTGCTAAGCAACTGGAGCATCATCTGTGCTGAGCTCTC GCATCTAATTATCCCATCACAGCAGCCGAGAAGGGTTTGGGGAGCT SEQ ID GGGAAACAGCTCCCGTAGGGCGGGGGCGCCCCAGCGCTCCCGTTGCTATGGCGACCTGGGT NO: 45 CCCCCGGGATTCTTTCTGCCTTGTTGCCGCGGAGACAGACTCCGCCCCCACCCCAGCGCAGC CGCTCTGGAGCCCGAAGGGGTTAAACCTGAATCGCGGAGGAGGAGGC SEQ ID GAAGCCGCCGCCTCCCCGCCGGACACCGTCGCCAAGTGCGGCGGGCGGAGCTAGAGCCGTA NO: 46 GCCAATCGAGGAACGGCAGCCTACAAGCCTCGTGTTGATTGGCTACTGCAGACGAGGAGGG CGGTGCTAGTAGGAGGGCACAGGCCCAGGGTGTCCTCGCAACGGGCGT SEQ ID CACACAGCGGTCGCTCCATAAGGGGGCCCCGCCTCTGGGCGGTGCCTGAAAGCGTATTTGC NO: 47 GCATGCGTTCTCGCCTTCGCTCGTTTCGTATACTGCACCAAAGAGCGCCTACCCTGGGGCGG GGCTCCCCATTTCATCCAATCAGAGCGTATCAACAGTCCTACCATCT SEQ ID GCCCACGGTTCTCCCAAGCTCACCGGCAACTGCCCAGGGCGCAGGCGCGGGACTGCGCTAC NO: 48 GGACTACATCTCCCGGCAGGCCACACGCCGCCCGCCGGGCTGTGCGCCCACAGGGATGCTG ACGTGGGAGGGGCTGGGACTCTTCCTGGCTTCCAACCAGCCTCAAGCT SEQ ID GCCGCCAGAAGTCCCGCCCACACAATTGAGACCTCATTAGTCGTCTCTCTGCTAGACCAATG NO: 49 GCTACACTCGCTGCCCTGCCCCCGCAGTGTCTTCTGGGTAATGTAGTTCTCACGTTGCTGCCT GTGTCGCCCGCAGTGTCTTCTGGGTAATGTAGTTCCCACGCTGCT SEQ ID CAGCCGCAGCCAAGCATCCCACGGAGCCTCCCCCCGCGCCCGTCGCCGTGGCGACCGCCGG NO: 50 GGCCACGCAGCACCGCCCCTTCCTCGCGACGTGGCCCCGCCCTCTGAGAACCCGGAAGCGG GAGTCTCGCGCCAGCTGAGCGGCGGTCGGGCGGGGGGAGCGCGGCGGC SEQ ID GGGAGGAAGCCCGCCCTGCCAGGGGCCGGGTCTGGAACCTGTTCATCCGGCTGCACTCAGC NO: 51 ACTGTGAGATCGCTTCTTCTGTCACTCAGTGCCCAGGAGGCGGGACCTGGAGGGCTACCCA ATCAAAGTCGTGGGCGGGTTCCTGAGAATTGTCAATCAGGCGCGAGGC SEQ ID CAGTTAATGCAAAATGGTCGCTATGGCAACACACGTAGCCGCCCTAGACCGCGGCCCGGAA NO: 52 GTGAAGACAACTTTCCAGGAGCCTGCGCACTTAGCGGGGAGGGCAAACGTTTGAAAAACGT TTCTGATTGGTTAAAAAAGAACAGTGGACGAGGGCTGAGAAAAGAAGT SEQ ID GGGCCGCGCGCGGGGCGTGGTCAGCCGGAGCTGTGACGCACCCGGGACGCAAGCCGAGGG NO: 53 CTCGGTTTCCACGGCAACAGGCGCTGGGCCCCTGTTTTTCCGCTCGCGCTCGTGCGTCACTT CCGGTCGCTCCCCTCTTTTTTTCAGCCTTGTGTAGGATAGGTTCCGAT SEQ ID TCATCTACAAAACAAATGAGGCCCTGCTCGCGGTTGCCATGGTACCGGGTGCCCAGCCTCC NO: 54 CTGCAGGATGATTGGCCAAGAAGCCCGCTGCTCCCGCCTTGGCCCCGCCCCTCCACCCCGCC ACTGGCTCAGAGCAAAGCCCCAGCAACTGGGCAGCCAATCCCCTCCC SEQ ID CCACCCCTGGGCTAAGAAACTCAGGCCTGTCACTAGGGAACCAAGTTGCTGTGGCAACCCT NO: 55 GTGCTACCGTTGCCATGACGCCAGCCACCCACCCACCCACTACCAGGTCTGTGTGCAGCTCA GGATGAAAATGGAGGGAGGGGCAGGGCTCTAGGACAGAAGAGGAAAT -43- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence SEQ ID TGTGGGGGTGGAGGGGAGATGATAGGACAGATCACCGAGTTGCCTAGAGACCTGGAGACC NO: 56 GACCCATCCGGGTCGCCTTCCCTGGTGCGCTCTCGTCGGCTCCATCCCTGGTTGCCATGGAG ACAGGAGGCGGTTGCCACGGAGACCGACGACTGCCAGGACCAGCCAAT SEQ ID ATTTATTCTCTATAGTTCCACCTCTCCGTCATTTTCCCGAGCCTGGATCTTTATTGCTTTACG NO: 57 ACCATACGTCGTGAAATAAGAAGGTGTTGCGGCAGTACTGGCGGAAGCTAGCCTTGCGTTT TGCGGCAGCAATATGAGCTAGGTCCGGATCCTGTTAGACACCGGCG SEQ ID GTCAGTTTCAGGGTAAACAGGCAAGATGGGTGGTGGGGGAAGGCGGGGAAGGGTGGACTG NO: 58 TTGCCACGGCAACAAAGGATTTCAGTGATGAGTATCCATGGTGATTGTTGCTACATTCTGAG TGGCTTTAAATGCTTTATTTAAAATACATAACAATCGTGCAGCTGCTG SEQ ID ATCCCCATGGTAACCAAGGGAACGGGGGACACTGGTTGCCATAGTGACTATGAGAGACCTG NO: 59 TGCAGTCACATGTCTACTGTTGCTATGGTGACTGTCCGGGCTGGAGTGGATCCCAAAGAGG GGGTAGGAGAGGGGAGGATCTTTCTTCTCCCCACAACCCACCATCAAA SEQ ID AATTGCTCAACTGTGACTGCCAGGGCGTTACCATGGTTACTGGGTAGCACTTGTGGCTATGG NO: 60 TAACAGGAAGCTGCCTGTTGTCTCGGCAACGAGCAAATTGGTAAGGGATGGAGTGGCCCCT GATTGGTGCAGAAGCAGAGCATTTCTTGAGGGGAGGGGGTCAGATCA SEQ ID CAACTGCCCGAGTCCTCCTGCAGCTGCTGCGGCTCGCGGCCCTCGCCTGAAAGCGGGCGTCT NO: 61 GATTGGTGTTTCCCGGGAGACGGGCTCCTCTAGCTGATGGAGCTGGTGCGCCGGCGCGCGC GCTCCCGGGTTGGCGCGCGACTGGGAGGCCGGGGGCGCGCTGCGGCC SEQ ID CGCGGGAACGGCTCCCTCCGCCGCCGCTCCCGCCGCTGCCGCCGTTGCCCGGGCCCCGCCG NO: 62 CCGTTGCTAGGCGACCGCTGCTGCCGTGGCCGCCTCTGTCACGAGCCCTGTCGCCCGGAGAC AGCGCGAGAGAGACGGGGGAGGGGGGCAAGGGGACCCCCAAAACAAA SEQ ID GTCTCAAGCTAGCACGTGATCGGCTGAATGCCTGCCAGCCTCTTTCTTGTTGATCCTCCGGA NO: 63 GACCATCTGTACTGGGGGCATTGATTAGAGTGTGTCTGCTGGGATTACATCTTTTCTGTTGC CATGCCAACTAATCAGCTGATTTTGGTTACCACAGAAACAAAATGT SEQ ID CTTCCGGCTCGCCGCTTCCGGGTGTGACGCATACTGCAGTCCCCCTTTTTCCCTTCCACGGCA NO: 64 CCAAATGCGTCAAAGCGCAGGCGTCGCTGGATTAGTTCCGCCGTAACGTGACAGCGCGCAG GCGCTGAAAGAAAGAGAAACAAATTTGGCGGAAGGGGTGTCACTGC SEQ ID CGCTTCCCGGCTGCCTTTGTGGCCGCAGCTTCTCGCCGCCGAGCCGAGGGCCGGCGGGGGC NO: 65 GCGGCGCGCACGGCCGAGCGATGCCCAGCTCGCTGTTCGCAGACCTGGAGCGCAACGGCAG CGGCGGCGGCGGCGGCGGCAGCAGCGGAGGGGGAGAGACCCTGGATGA SEQ ID ACGCCGCCGGAAGCGCGACCCGCACTTCCGGTAGCGGCATTGCGCGGAGGGCCGCCTTGGG NO: 66 AGCTTGCTGGGAGTTGTAGTTCTGTGCCGCCCTCTGGCGGAAAGGCCGGCGATCCTTGCATC ACGTGACGGGGCCGCATGGGCCGCCGGGATGTGTAGTCCGCAGGAGT SEQ ID CGATCCGGGCCGAGGTGACTGGAAGAAGCCGTAGTACGCAGGAGCAAGGGCCGAGAGGCG NO: 67 AGCGCCGAACGCTATCAGGAGTGGCTAGCCGATTGTCGAGCTCGGGAAACTGCGTGTTTAC GTAGGGTAAGAAGAACGCTATCTCGAAGGCTTCGTACTTGGCCGTGGTA SEQ ID TGTTTCCTCCCAGAGCAGGCAGACCCTCCAGTCCCAGCTGGGACTGCTCCCACTGACAGCTG NO: 68 TTTGGGGGCAAAGCCCCTCCCCCATGGCAAGCTCCCTGCTGTTCCTGCTCCTGTCACCTTGG CAACCGGCTTCTTCAGGCTCTGCAAATAGAAAAGGTCCCTTATGCC SEQ ID CTTCGCTTTCGGCGCCATCTTGTGAAAAGGGTCTCCAATGCTCGTTCCCACGGGCTTATAGC NO: 69 GCCAAAGAGCACTAAAGACTCGCGATGCTTTGTACTTAGAGCTGATTGGGTAATTTGCAGA GCGGCGCCCTCTGGGAACGGTAGTTAGGTTTAATTTCTTTTTCGTGC SEQ ID GCTATCTGTGTCATCCCTACTTCCCAGGCTCCCCTGCTCCTCTCTTGTTTCCACGGCAACCAG NO: 70 TCTGGCGACAGCTCCAGAGCATCCCCCTCCCCTCCCCAGTCCTGGGTACCACTAGGGGTTGA TCCAAACCACACGCCATAGCTATTTTTAGCCAAAGTCCCTCCTCC SEQ ID TTACTGGAGAACATCAGGACCTTCTCCATGGAAACCGCCGCAGGACAGCTCAGCATCCATC NO: 71 CATTCAAGGGATGGTTCCCATGGCAACAGCCCGCCTGGCTGCGCTGAACTGGTGGTGACGC GCGTGCCTGAGGCTGTAATTGCAGGCTCTTCTGCTGCTGCAGCAGGAG -44- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence SEQ ID AGCATTTTCCTCATCTGCCACCAGGTGGCAGGTGGATCCACTTTTCGGAACGCGACCCCGAC NO: 72 CCCGCCCTACCGGAAGCTGTCATGTAAAGGAAATCTCTCTGGCCACGCCCAGAGTTCAGCA CCATGGCCACGGACAGCGACACCGCCCAGTTCGGTCCCATGACTCGC SEQ ID CTTGGCACTGAGTCCAGAAGCTGAGCTTGGTAACTGGGGAGGGGGAAGAAAAGGAGGCGA NO: 73 GTTTCCATGGCAACGCTGGTGCTGCGTGCAAATGGAACAAGCGTGCATCTTCCCAAGGGAG GAAGGGAGCACGGAAAGTGGAAATGGAGGGGGAAGGGCAGTGTAGCTTC SEQ ID AACTACAGCTCACTCACCATCTTGGGCGGCGGGAGGAGAGAGAAAGGAAAGGGAATTGTG NO: 74 GGTAATATGTATGCGGCCTCGGAGATCGCGAGAGTTGATACCGGCACGGGATTTCGGATTT AAAGCAACAGCATTCCTATAAAGCTAAAAATCGAGGCGGGGCTGAGAGG SEQ ID GGCATAAGGGACCTTTTCTATTTGCAGAGCCTGAAGAAGCCGGTTGCCAAGGTGACAGGAG NO: 75 CAGGAACAGCAGGGAGCTTGCCATGGGGGAGGGGCTTTGCCCCCAAACAGCTGTCAGTGG GAGCAGTCCCAGCTGGGACTGGAGGGTCTGCCTGCTCTGGGAGGAAACA SEQ ID GAAGCTACACTGCCCTTCCCCCTCCATTTCCACTTTCCGTGCTCCCTTCCTCCCTTGGGAAGA NO: 76 TGCACGCTTGTTCCATTTGCACGCAGCACCAGCGTTGCCATGGAAACTCGCCTCCTTTTCTTC CCCCTCCCCAGTTACCAAGCTCAGCTTCTGGACTCAGTGCCAAG SEQ ID TGCTTTTTCTTTGTTTGTTGTTGACTAGGCTGAATGGTGGGGTTTTTTTTAAGTTAATTATAA NO: 77 ACGAAGTTGAAATAGCAAACAAGCCAACAGCTTGTCCCCCCCACCAAAAGAAAAATTAGCC CCACACAAGCGCCTTCTGCTGCAACAGATGCCCAGATCACCCCTGG SEQ ID CTGCCCAGATGGCAGTTCCCCTTCCCCAGGGACCAGTGATGCAGCAGCTCGTGTAGCCTGC NO: 78 AGTTGCCATGGTGATAGCCCTCCTTTGGCTTTCCATGGGGTGGGGGATGACAGGGAGGGTG TGAGTGTGGTGAGTGTGTCCCATTTTCCGCTCCAGGTGAGGAGAGCTT SEQ ID AATTAAGTGAACAAAATTACAAGGCAGCTTATTCAAAGGGGAAAATTGTTTTTGGATACCT NO: 79 TATTACATTAATCGTCTATATGCAAATCATTTTTTCTAAATGCAAATGAGTCTCCATTATTAG AACAGATGCATGGAAACGCACCGTGAATATTCAAGTCAGCTCCCTG SEQ ID AAGAGATATTTAATCTTTATGAAGCACCTGTGTACTAAATATTTATGATATACCAAATATAC NO: 80 ACGTGATTCAATATATGAGTCTCAAAATATTTGGGCACTTAATATTCACGGGGTCTTATTTG GCCACACATAGATAACACACATTCTGGTCCCATGTTTTCTCTGCCA ATCGGAACCTATCCTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACG AGCGCGAGCGGAAAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTT SEQ ID GCGTCCCGGGTGCGTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCCAGCTCCCCAAA NO: 237 CCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAGATGATGCTCCA GTTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCAGAGCAGCCAGT GAGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCC ATCGGAACCTATCCTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACG AGCGCGAGCGGAAAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTT SEQ ID GCGTCCCGGGTGCGTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCCGGGAGGGGATT NO: 238 GGCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGGGCGGGGCCAAG GCGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCACCCGGTACCATG GCAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGA ATCGGAACCTATCCTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACG AGCGCGAGCGGAAAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTT SEQ ID GCGTCCCGGGTGCGTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCCATTTCCTCTTCT NO: 239 GTCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGACCTGGTAGTGGG TGGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCAACTTGGTTCCC TAGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGG ATCGGAACCTATCCTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACG AGCGCGAGCGGAAAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTT SEQ ID GCGTCCCGGGTGCGTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCCTTTGATGGTGG NO: 240 GTTGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCCACTCCAGCCCG GACAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAGTCACTATGGCA ACCAGTGTCCCCCGTTCCCTTGGTTACCATGGGGAT -45- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence ATCGGAACCTATCCTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACG AGCGCGAGCGGAAAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTT SEQ ID GCGTCCCGGGTGCGTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCCTGATCTGACCC NO: 241 CCTCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATCCCTTACCAATT TGCTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGCTACCCAGTAA CCATGGTAACGCCCTGGCAGTCACAGTTGAGCAATT AGCTCCCCAAACCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAG ATGATGCTCCAGTTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCA SEQ ID GAGCAGCCAGTGAGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCCATCGGAACCTAT NO: 242 CCTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACGAGCGCGAGCGG AAAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTTGCGTCCCGGGTG CGTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCC AGCTCCCCAAACCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAG ATGATGCTCCAGTTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCA SEQ ID GAGCAGCCAGTGAGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCCGGGAGGGGATTG NO: 243 GCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGGGCGGGGCCAAGG CGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCACCCGGTACCATGG CAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGA AGCTCCCCAAACCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAG ATGATGCTCCAGTTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCA SEQ ID GAGCAGCCAGTGAGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCCATTTCCTCTTCTG NO: 244 TCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGACCTGGTAGTGGGT GGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCAACTTGGTTCCCT AGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGG AGCTCCCCAAACCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAG ATGATGCTCCAGTTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCA SEQ ID GAGCAGCCAGTGAGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCCTTTGATGGTGGG NO: 245 TTGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCCACTCCAGCCCGG ACAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAGTCACTATGGCAA CCAGTGTCCCCCGTTCCCTTGGTTACCATGGGGAT AGCTCCCCAAACCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAG ATGATGCTCCAGTTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCA SEQ ID GAGCAGCCAGTGAGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCCTGATCTGACCCC NO: 246 CTCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATCCCTTACCAATTT GCTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGCTACCCAGTAAC CATGGTAACGCCCTGGCAGTCACAGTTGAGCAATT GGGAGGGGATTGGCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGG GCGGGGCCAAGGCGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCA SEQ ID CCCGGTACCATGGCAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGAATCGGAACCTATC NO: 247 CTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACGAGCGCGAGCGGA AAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTTGCGTCCCGGGTGC GTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCC GGGAGGGGATTGGCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGG GCGGGGCCAAGGCGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCA SEQ ID CCCGGTACCATGGCAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGAAGCTCCCCAAAC NO: 248 CCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAGATGATGCTCCAG TTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCAGAGCAGCCAGTG AGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCC GGGAGGGGATTGGCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGG GCGGGGCCAAGGCGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCA SEQ ID CCCGGTACCATGGCAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGAATTTCCTCTTCTG NO: 249 TCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGACCTGGTAGTGGGT GGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCAACTTGGTTCCCT AGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGG -46- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence GGGAGGGGATTGGCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGG GCGGGGCCAAGGCGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCA SEQ ID CCCGGTACCATGGCAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGATTTGATGGTGGGT NO: 250 TGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCCACTCCAGCCCGGA CAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAGTCACTATGGCAAC CAGTGTCCCCCGTTCCCTTGGTTACCATGGGGAT GGGAGGGGATTGGCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGG GCGGGGCCAAGGCGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCA SEQ ID CCCGGTACCATGGCAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGATGATCTGACCCCC NO: 251 TCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATCCCTTACCAATTTG CTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGCTACCCAGTAACC ATGGTAACGCCCTGGCAGTCACAGTTGAGCAATT ATTTCCTCTTCTGTCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGAC CTGGTAGTGGGTGGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCA SEQ ID ACTTGGTTCCCTAGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGGATCGGAACCTATCCTA NO: 252 CACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACGAGCGCGAGCGGAAAA ACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTTGCGTCCCGGGTGCGTC ACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCC ATTTCCTCTTCTGTCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGAC CTGGTAGTGGGTGGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCA SEQ ID ACTTGGTTCCCTAGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGGAGCTCCCCAAACCCTT NO: 253 CTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAGATGATGCTCCAGTTGC TTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCAGAGCAGCCAGTGAGCA GCTCGGCAGGGCAGGGAGAAGACGCAACTCCC ATTTCCTCTTCTGTCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGAC CTGGTAGTGGGTGGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCA SEQ ID ACTTGGTTCCCTAGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGGGGGAGGGGATTGGCT NO: 254 GCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGGGCGGGGCCAAGGCGG GAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCACCCGGTACCATGGCAA CCGCGAGCAGGGCCTCATTTGTTTTGTAGATGA ATTTCCTCTTCTGTCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGAC CTGGTAGTGGGTGGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCA SEQ ID ACTTGGTTCCCTAGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGGTTTGATGGTGGGTTGT NO: 255 GGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCCACTCCAGCCCGGACA GTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAGTCACTATGGCAACCA GTGTCCCCCGTTCCCTTGGTTACCATGGGGAT ATTTCCTCTTCTGTCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGAC CTGGTAGTGGGTGGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCA SEQ ID ACTTGGTTCCCTAGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGGTGATCTGACCCCCTCC NO: 256 CCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATCCCTTACCAATTTGCTC GTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGCTACCCAGTAACCATG GTAACGCCCTGGCAGTCACAGTTGAGCAATT TTTGATGGTGGGTTGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCC ACTCCAGCCCGGACAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAG SEQ ID TCACTATGGCAACCAGTGTCCCCCGTTCCCTTGGTTACCATGGGGATATCGGAACCTATCCT NO: 257 ACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACGAGCGCGAGCGGAAA AACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTTGCGTCCCGGGTGCGT CACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCC TTTGATGGTGGGTTGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCC ACTCCAGCCCGGACAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAG SEQ ID TCACTATGGCAACCAGTGTCCCCCGTTCCCTTGGTTACCATGGGGATAGCTCCCCAAACCCT NO: 258 TCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAGATGATGCTCCAGTTG CTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCAGAGCAGCCAGTGAGC AGCTCGGCAGGGCAGGGAGAAGACGCAACTCCC -47- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence TTTGATGGTGGGTTGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCC ACTCCAGCCCGGACAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAG SEQ ID TCACTATGGCAACCAGTGTCCCCCGTTCCCTTGGTTACCATGGGGATGGGAGGGGATTGGCT NO: 259 GCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGGGCGGGGCCAAGGCGG GAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCACCCGGTACCATGGCAA CCGCGAGCAGGGCCTCATTTGTTTTGTAGATGA TTTGATGGTGGGTTGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCC ACTCCAGCCCGGACAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAG SEQ ID TCACTATGGCAACCAGTGTCCCCCGTTCCCTTGGTTACCATGGGGATATTTCCTCTTCTGTCC NO: 260 TAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGACCTGGTAGTGGGTGGG TGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCAACTTGGTTCCCTAGT GACAGGCCTGAGTTTCTTAGCCCAGGGGTGG TTTGATGGTGGGTTGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCC ACTCCAGCCCGGACAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAG SEQ ID TCACTATGGCAACCAGTGTCCCCCGTTCCCTTGGTTACCATGGGGATTGATCTGACCCCCTC NO: 261 CCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATCCCTTACCAATTTGCT CGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGCTACCCAGTAACCAT GGTAACGCCCTGGCAGTCACAGTTGAGCAATT TGATCTGACCCCCTCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATC CCTTACCAATTTGCTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGC SEQ ID TACCCAGTAACCATGGTAACGCCCTGGCAGTCACAGTTGAGCAATTATCGGAACCTATCCT NO: 262 ACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACGAGCGCGAGCGGAAA AACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTTGCGTCCCGGGTGCGT CACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCC TGATCTGACCCCCTCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATC CCTTACCAATTTGCTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGC SEQ ID TACCCAGTAACCATGGTAACGCCCTGGCAGTCACAGTTGAGCAATTAGCTCCCCAAACCCTT NO: 263 CTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAGATGATGCTCCAGTTGC TTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCAGAGCAGCCAGTGAGCA GCTCGGCAGGGCAGGGAGAAGACGCAACTCCC TGATCTGACCCCCTCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATC CCTTACCAATTTGCTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGC SEQ ID TACCCAGTAACCATGGTAACGCCCTGGCAGTCACAGTTGAGCAATTGGGAGGGGATTGGCT NO: 264 GCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGGGCGGGGCCAAGGCGG GAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCACCCGGTACCATGGCAA CCGCGAGCAGGGCCTCATTTGTTTTGTAGATGA TGATCTGACCCCCTCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATC CCTTACCAATTTGCTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGC SEQ ID TACCCAGTAACCATGGTAACGCCCTGGCAGTCACAGTTGAGCAATTATTTCCTCTTCTGTCC NO: 265 TAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGACCTGGTAGTGGGTGGG TGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCAACTTGGTTCCCTAGT GACAGGCCTGAGTTTCTTAGCCCAGGGGTGG TGATCTGACCCCCTCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATC CCTTACCAATTTGCTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGC SEQ ID TACCCAGTAACCATGGTAACGCCCTGGCAGTCACAGTTGAGCAATTTTTGATGGTGGGTTGT NO: 266 GGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCCACTCCAGCCCGGACA GTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAGTCACTATGGCAACCA GTGTCCCCCGTTCCCTTGGTTACCATGGGGAT CCCCTATAGTAGGCCAGCCTATGAACGCAACCGGCAAATTTCGACCAATCCGAGTCTAGCT CTTCTGGATTCCCAGCATGCAGCGCAGACCCTGATCCAATTGCTGTAAAGACGCATCCTTAG SEQ ID AGAGGCTCTCGGGAGTCCGAGAGAGCACTGCATTCTGGGATTTGTAGCCCCTATAGTAGGC NO: 267 CAGCCTATGAACGCAACCGGCAAATTTCGACCAATCCGAGTCTAGCTCTTCTGGATTCCCAG CATGCAGCGCAGACCCTGATCCAATTGCTGTAAAGACGCATCCTTAGAGAGGCTCTCGGGA GTCCGAGAGAGCACTGCATTCTGGGATTTGTAG -48- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence AGGATGGTAGAGGAAGTCCCGCCCTGACGTTGGTGAGGACCAACGGAAACGCCTATTTCCT GGGTTTTCATTGGCCCAGAGCCGCCAAGTTTCCTGGGTAATGTAGTTCCCACGGCACCAACA SEQ ID CTAGTAAGCGGCGTCTCGCTTCACCTCCAGGTTAAAAGCCCAGAGAAAGGATGGTAGAGGA NO: 268 AGTCCCGCCCTGACGTTGGTGAGGACCAACGGAAACGCCTATTTCCTGGGTTTTCATTGGCC CAGAGCCGCCAAGTTTCCTGGGTAATGTAGTTCCCACGGCACCAACACTAGTAAGCGGCGT CTCGCTTCACCTCCAGGTTAAAAGCCCAGAGAA ACCCAGTCTCAGTAGCTTGGTAGTTACCATGGCTCCCAGTGCTGTGCGTCTGACGTCATTCT GCGGCGCTGGCTGATGGCGCAATCAGTTGCGGCGTCCTGTGAGCGCGGGGATGCTGGGAGG SEQ ID AGGGTGAAATTTAGCCATCGGTGTGTGGCAGGGTCATGAAAAAGCGGACCCAGTCTCAGTA NO: 269 GCTTGGTAGTTACCATGGCTCCCAGTGCTGTGCGTCTGACGTCATTCTGCGGCGCTGGCTGA TGGCGCAATCAGTTGCGGCGTCCTGTGAGCGCGGGGATGCTGGGAGGAGGGTGAAATTTAG CCATCGGTGTGTGGCAGGGTCATGAAAAAGCGG AGCTCCCCAAACCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAG ATGATGCTCCAGTTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCA SEQ ID GAGCAGCCAGTGAGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCCAGCTCCCCAAAC NO: 270 CCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACAGATGATGCTCCAG TTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCTCCAGAGCAGCCAGTG AGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCC GCCTCCTCCTCCGCGATTCAGGTTTAACCCCTTCGGGCTCCAGAGCGGCTGCGCTGGGGTGG GGGCGGAGTCTGTCTCCGCGGCAACAAGGCAGAAAGAATCCCGGGGGACCCAGGTCGCCA SEQ ID TAGCAACGGGAGCGCTGGGGCGCCCCCGCCCTACGGGAGCTGTTTCCCGCCTCCTCCTCCGC NO: 271 GATTCAGGTTTAACCCCTTCGGGCTCCAGAGCGGCTGCGCTGGGGTGGGGGCGGAGTCTGT CTCCGCGGCAACAAGGCAGAAAGAATCCCGGGGGACCCAGGTCGCCATAGCAACGGGAGC GCTGGGGCGCCCCCGCCCTACGGGAGCTGTTTCCC ACGCCCGTTGCGAGGACACCCTGGGCCTGTGCCCTCCTACTAGCACCGCCCTCCTCGTCTGC AGTAGCCAATCAACACGAGGCTTGTAGGCTGCCGTTCCTCGATTGGCTACGGCTCTAGCTCC SEQ ID GCCCGCCGCACTTGGCGACGGTGTCCGGCGGGGAGGCGGCGGCTTCACGCCCGTTGCGAGG NO: 272 ACACCCTGGGCCTGTGCCCTCCTACTAGCACCGCCCTCCTCGTCTGCAGTAGCCAATCAACA CGAGGCTTGTAGGCTGCCGTTCCTCGATTGGCTACGGCTCTAGCTCCGCCCGCCGCACTTGG CGACGGTGTCCGGCGGGGAGGCGGCGGCTTC AGATGGTAGGACTGTTGATACGCTCTGATTGGATGAAATGGGGAGCCCCGCCCCAGGGTAG GCGCTCTTTGGTGCAGTATACGAAACGAGCGAAGGCGAGAACGCATGCGCAAATACGCTTT SEQ ID CAGGCACCGCCCAGAGGCGGGGCCCCCTTATGGAGCGACCGCTGTGTGAGATGGTAGGACT NO: 273 GTTGATACGCTCTGATTGGATGAAATGGGGAGCCCCGCCCCAGGGTAGGCGCTCTTTGGTG CAGTATACGAAACGAGCGAAGGCGAGAACGCATGCGCAAATACGCTTTCAGGCACCGCCC AGAGGCGGGGCCCCCTTATGGAGCGACCGCTGTGTG AGCTTGAGGCTGGTTGGAAGCCAGGAAGAGTCCCAGCCCCTCCCACGTCAGCATCCCTGTG GGCGCACAGCCCGGCGGGCGGCGTGTGGCCTGCCGGGAGATGTAGTCCGTAGCGCAGTCCC SEQ ID GCGCCTGCGCCCTGGGCAGTTGCCGGTGAGCTTGGGAGAACCGTGGGCAGCTTGAGGCTGG NO: 274 TTGGAAGCCAGGAAGAGTCCCAGCCCCTCCCACGTCAGCATCCCTGTGGGCGCACAGCCCG GCGGGCGGCGTGTGGCCTGCCGGGAGATGTAGTCCGTAGCGCAGTCCCGCGCCTGCGCCCT GGGCAGTTGCCGGTGAGCTTGGGAGAACCGTGGGC AGCAGCGTGGGAACTACATTACCCAGAAGACACTGCGGGCGACACAGGCAGCAACGTGAG AACTACATTACCCAGAAGACACTGCGGGGGCAGGGCAGCGAGTGTAGCCATTGGTCTAGCA SEQ ID GAGAGACGACTAATGAGGTCTCAATTGTGTGGGCGGGACTTCTGGCGGCAGCAGCGTGGGA NO: 275 ACTACATTACCCAGAAGACACTGCGGGCGACACAGGCAGCAACGTGAGAACTACATTACCC AGAAGACACTGCGGGGGCAGGGCAGCGAGTGTAGCCATTGGTCTAGCAGAGAGACGACTA ATGAGGTCTCAATTGTGTGGGCGGGACTTCTGGCGGC GCCGCCGCGCTCCCCCCGCCCGACCGCCGCTCAGCTGGCGCGAGACTCCCGCTTCCGGGTTC TCAGAGGGCGGGGCCACGTCGCGAGGAAGGGGCGGTGCTGCGTGGCCCCGGCGGTCGCCA SEQ ID CGGCGACGGGCGCGGGGGGAGGCTCCGTGGGATGCTTGGCTGCGGCTGGCCGCCGCGCTCC NO: 276 CCCCGCCCGACCGCCGCTCAGCTGGCGCGAGACTCCCGCTTCCGGGTTCTCAGAGGGCGGG GCCACGTCGCGAGGAAGGGGCGGTGCTGCGTGGCCCCGGCGGTCGCCACGGCGACGGGCG CGGGGGGAGGCTCCGTGGGATGCTTGGCTGCGGCTG -49- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence GCCTCGCGCCTGATTGACAATTCTCAGGAACCCGCCCACGACTTTGATTGGGTAGCCCTCCA GGTCCCGCCTCCTGGGCACTGAGTGACAGAAGAAGCGATCTCACAGTGCTGAGTGCAGCCG SEQ ID GATGAACAGGTTCCAGACCCGGCCCCTGGCAGGGCGGGCTTCCTCCCGCCTCGCGCCTGAT NO: 277 TGACAATTCTCAGGAACCCGCCCACGACTTTGATTGGGTAGCCCTCCAGGTCCCGCCTCCTG GGCACTGAGTGACAGAAGAAGCGATCTCACAGTGCTGAGTGCAGCCGGATGAACAGGTTCC AGACCCGGCCCCTGGCAGGGCGGGCTTCCTCCC ACTTCTTTTCTCAGCCCTCGTCCACTGTTCTTTTTTAACCAATCAGAAACGTTTTTCAAACGT TTGCCCTCCCCGCTAAGTGCGCAGGCTCCTGGAAAGTTGTCTTCACTTCCGGGCCGCGGTCT SEQ ID AGGGCGGCTACGTGTGTTGCCATAGCGACCATTTTGCATTAACTGACTTCTTTTCTCAGCCC NO: 278 TCGTCCACTGTTCTTTTTTAACCAATCAGAAACGTTTTTCAAACGTTTGCCCTCCCCGCTAAG TGCGCAGGCTCCTGGAAAGTTGTCTTCACTTCCGGGCCGCGGTCTAGGGCGGCTACGTGTGT TGCCATAGCGACCATTTTGCATTAACTG ATCGGAACCTATCCTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACG AGCGCGAGCGGAAAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTT SEQ ID GCGTCCCGGGTGCGTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCCATCGGAACCTA NO: 279 TCCTACACAAGGCTGAAAAAAAGAGGGGAGCGACCGGAAGTGACGCACGAGCGCGAGCGG AAAAACAGGGGCCCAGCGCCTGTTGCCGTGGAAACCGAGCCCTCGGCTTGCGTCCCGGGTG CGTCACAGCTCCGGCTGACCACGCCCCGCGCGCGGCCC GGGAGGGGATTGGCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGG GCGGGGCCAAGGCGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCA SEQ ID CCCGGTACCATGGCAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGAGGGAGGGGATTG NO: 280 GCTGCCCAGTTGCTGGGGCTTTGCTCTGAGCCAGTGGCGGGGTGGAGGGGCGGGGCCAAGG CGGGAGCAGCGGGCTTCTTGGCCAATCATCCTGCAGGGAGGCTGGGCACCCGGTACCATGG CAACCGCGAGCAGGGCCTCATTTGTTTTGTAGATGA ATTTCCTCTTCTGTCCTAGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGAC CTGGTAGTGGGTGGGTGGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCA SEQ ID ACTTGGTTCCCTAGTGACAGGCCTGAGTTTCTTAGCCCAGGGGTGGATTTCCTCTTCTGTCCT NO: 281 AGAGCCCTGCCCCTCCCTCCATTTTCATCCTGAGCTGCACACAGACCTGGTAGTGGGTGGGT GGGTGGCTGGCGTCATGGCAACGGTAGCACAGGGTTGCCACAGCAACTTGGTTCCCTAGTG ACAGGCCTGAGTTTCTTAGCCCAGGGGTGG ATTGGCTGGTCCTGGCAGTCGTCGGTCTCCGTGGCAACCGCCTCCTGTCTCCATGGCAACCA GGGATGGAGCCGACGAGAGCGCACCAGGGAAGGCGACCCGGATGGGTCGGTCTCCAGGTC SEQ ID TCTAGGCAACTCGGTGATCTGTCCTATCATCTCCCCTCCACCCCCACAATTGGCTGGTCCTG NO: 282 GCAGTCGTCGGTCTCCGTGGCAACCGCCTCCTGTCTCCATGGCAACCAGGGATGGAGCCGA CGAGAGCGCACCAGGGAAGGCGACCCGGATGGGTCGGTCTCCAGGTCTCTAGGCAACTCGG TGATCTGTCCTATCATCTCCCCTCCACCCCCACA CGCCGGTGTCTAACAGGATCCGGACCTAGCTCATATTGCTGCCGCAAAACGCAAGGCTAGC TTCCGCCAGTACTGCCGCAACACCTTCTTATTTCACGACGTATGGTCGTAAAGCAATAAAGA SEQ ID TCCAGGCTCGGGAAAATGACGGAGAGGTGGAACTATAGAGAATAAATCGCCGGTGTCTAA NO: 283 CAGGATCCGGACCTAGCTCATATTGCTGCCGCAAAACGCAAGGCTAGCTTCCGCCAGTACT GCCGCAACACCTTCTTATTTCACGACGTATGGTCGTAAAGCAATAAAGATCCAGGCTCGGG AAAATGACGGAGAGGTGGAACTATAGAGAATAAAT CAGCAGCTGCACGATTGTTATGTATTTTAAATAAAGCATTTAAAGCCACTCAGAATGTAGCA ACAATCACCATGGATACTCATCACTGAAATCCTTTGTTGCCGTGGCAACAGTCCACCCTTCC SEQ ID CCGCCTTCCCCCACCACCCATCTTGCCTGTTTACCCTGAAACTGACCAGCAGCTGCACGATT NO: 284 GTTATGTATTTTAAATAAAGCATTTAAAGCCACTCAGAATGTAGCAACAATCACCATGGAT ACTCATCACTGAAATCCTTTGTTGCCGTGGCAACAGTCCACCCTTCCCCGCCTTCCCCCACC ACCCATCTTGCCTGTTTACCCTGAAACTGAC TTTGATGGTGGGTTGTGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCC ACTCCAGCCCGGACAGTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAG SEQ ID TCACTATGGCAACCAGTGTCCCCCGTTCCCTTGGTTACCATGGGGATTTTGATGGTGGGTTG NO: 285 TGGGGAGAAGAAAGATCCTCCCCTCTCCTACCCCCTCTTTGGGATCCACTCCAGCCCGGACA GTCACCATAGCAACAGTAGACATGTGACTGCACAGGTCTCTCATAGTCACTATGGCAACCA GTGTCCCCCGTTCCCTTGGTTACCATGGGGAT -50- ^{Docket No. 421688-718021 (718WO1)} SEQ ID _NO: ^Sequence TGATCTGACCCCCTCCCCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATC CCTTACCAATTTGCTCGTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGC SEQ ID TACCCAGTAACCATGGTAACGCCCTGGCAGTCACAGTTGAGCAATTTGATCTGACCCCCTCC NO: 286 CCTCAAGAAATGCTCTGCTTCTGCACCAATCAGGGGCCACTCCATCCCTTACCAATTTGCTC GTTGCCGAGACAACAGGCAGCTTCCTGTTACCATAGCCACAAGTGCTACCCAGTAACCATG GTAACGCCCTGGCAGTCACAGTTGAGCAATT SEQ ID TGGGGGTGGCTTTCTGAGGTTTCCATTGGGGGGCAGCCAGAGGCAGAGGGCAGGGGCTGGG NO: 360 ACTGCCTATGCATGCATGTTTGTGTGTGTTTGTGTGTGCGCAGGCGTGTTGTTGGCACGGAC GTGACTCTGCATTATCCGGGCCCGTAATGAGTCCTCATTGCAATGGG SEQ ID CCCATTGCAATGAGGACTCATTACGGGCCCGGATAATGCAGAGTCACGTCCGTGCCAACAA NO: 385 CACGCCTGCGCACACACAAACACACACAAACATGCATGCATAGGCAGTCCCAGCCCCTGCC CTCTGCCTCTGGCTGCCCCCCAATGGAAACCTCAGAAAGCCACCCCCA [0187] A polynucleotide encoding a CNS-enhancer of the presence disclosure may enhance transcriptional activity of a polynucleotide encoding a payload, wherein the polynucleotide encoding the payload is under transcriptional control of a promoter comprising the polynucleotide encoding the CNS-enhancer. An increase in cell transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target cell type (e.g., neurons) relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences. A CNS-enhancer (e.g., any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote cell transcription activity in a target CNS-cell type at a rate that is higher than the rate of transcription activity in a non-target cell type. In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote cell transcription activity in a target CNS-cell type at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5- fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity in a non-target cell type (e.g., hepatocytes). In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote cell transcription activity at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20- fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity of a different enhancer/promoter (e.g., enhancer/core promoter). An increase in tissue -51- ^{Docket No. 421688-718021 (718WO1)} transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target tissue relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences. A CNS-enhancer (e.g., any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote tissue transcription activity in a CNS tissue at a rate that is higher than the rate of transcription activity in a non-target tissue (e.g., liver tissue). In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote tissue transcription activity in a target CNS tissue at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than of the rate of tissue transcription activity in a non-target tissue. In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote tissue transcription activity at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20- fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of tissue transcription activity of a different enhancer/promoter (e.g., enhancer/core promoter). [0188] A CNS-enhancer of the presence disclosure may enhance transcription specificity in CNS cells or tissue of a payload under transcriptional control of the CNS-enhancer in a polynucleotide. An increase in cell transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target cell type (e.g., neurons) relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences. An increase in cell transcriptional specificity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) of cell transcription activity in a target cell type relative to one or more non- target cell types (e.g., hepatocytes). A CNS-enhancer (e.g., any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote cell transcription specificity in a target CNS-cell type (e.g., a neuron) over a non-target cell type (e.g., a hepatocyte), in which the rate of cell transcription activity is higher in the target CNS-cell type than the rate of cell transcription activity in a non-target cell type. In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote cell transcription specificity -52- ^{Docket No. 421688-718021 (718WO1)} in a target CNS-cell type over a non-target cell, in which the rate of cell transcription activity in a target CNS-cell type at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2- fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity in a non-target cell type. A CNS-enhancer of the presence disclosure may enhance tissue transcription specificity in CNS tissue of a payload under transcriptional control of the CNS-enhancer in a polynucleotide. An increase in tissue transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target tissue (e.g., CNS tissue) relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences. An increase in tissue transcriptional specificity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) of transcription activity in a target tissue (e.g., CNS tissue) relative to one or more non-target tissues (e.g., liver, serum, etc.). A CNS- enhancer (e.g., any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote tissue transcription specificity in a target CNS-cell type over a non-target cell, in which the rate of tissue transcription activity is higher in the target CNS-cell type than the rate of tissue transcription activity in a non-target cell type. In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote tissue transcription specificity in a target CNS-cell type over a non-target cell, in which the rate of tissue transcription activity in a target CNS-cell type at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5- fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of tissue transcription activity in a non-target cell type. [0189] The CNS-enhancers of the presence disclosure enhance transcription activity and transcription specificity in CNS cells or tissue of a payload under transcriptional control of the CNS-enhancer. An increase in cell transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target cell type relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences and an increase in cell transcriptional specificity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) of cell transcription activity for a target cell type relative to one or more non-target cell types. A CNS-enhancer (e.g., any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ -53- ^{Docket No. 421688-718021 (718WO1)} ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote cell transcription specificity in a target CNS-cell type over a non-target cell, in which the rate of cell transcription activity is higher in the target CNS-cell type than the rate of cell transcription activity in a non-target cell type. In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote cell transcription specificity in a target CNS-cell type over a non-target cell, in which the rate of cell transcription activity in a target CNS-cell type at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4- fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity in a non-target cell type. In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote cell transcription activity at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3- fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity when paired with a non-CNS enhancer/promoter (e.g., enhancer/core promoter) sequence. An increase in tissue transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target tissue relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences and an increase in tissue transcriptional specificity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) of tissue transcription activity for a target tissue relative to one or more non-target tissues. A CNS- enhancer (e.g., any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote tissue transcription specificity in a target CNS tissue over a non-target tissue, in which the rate of tissue transcription activity is higher in the target CNS tissue than the rate of tissue transcription activity in a non-target tissue. In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote tissue transcription specificity in a target CNS tissue over a non-target tissue, in which the rate of tissue transcription activity in a target tissue at a rate that is at least about 1-fold, at least about 1.1- fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least -54- ^{Docket No. 421688-718021 (718WO1)} about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of tissue transcription activity in a non-target tissue. In some embodiments, a CNS-enhancer (e.g., SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) may promote tissue transcription activity at a rate that is at least about 1- fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of tissue transcription activity when paired with a non-CNS enhancer/promoter (e.g., enhancer/core promoter) sequence. [0190] In some embodiments, a CNS-enhancer may comprise a sequence of any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385. In some embodiments, a CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385. In some embodiments, a CNS-enhancer may comprise a sequence having about 70%, about 72%, about 75%, about 78%, about 80%, about 82%, about 85%, about 87%, about 90%, about 92%, about 93%, about 95%, about 97%, about 98%, about 99%, or about 100% sequence identity to any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385. In some embodiments, a CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385. [0191] A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at -55- ^{Docket No. 421688-718021 (718WO1)} least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 1. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 1. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 1. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 2. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 2. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 2. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 3. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 3. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 70% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 72% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 75% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 78% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 80% sequence identity to SEQ ID NO: 4. A CNS- -56- ^{Docket No. 421688-718021 (718WO1)} enhancer may comprise a sequence having at least about 85% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 87% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 90% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 92% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 93% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 95% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 97% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 98% sequence identity to SEQ ID NO: 4. A CNS- enhancer may comprise a sequence having at least about 99% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 100% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 70% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 72% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 75% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 78% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 80% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 85% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 87% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 90% sequence identity to SEQ ID NO: 4. A CNS- enhancer may comprise a sequence having at least 92% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 93% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 95% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 97% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 98% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least 99% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 70% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 72% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 75% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 78% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 80% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 85% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 87% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 90% sequence identity to SEQ ID NO: 4. A CNS- -57- ^{Docket No. 421688-718021 (718WO1)} enhancer may comprise a sequence having about 92% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 93% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 95% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 97% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 98% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 99% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having about 100% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 70% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 72% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 75% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 78% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 80% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 85% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 87% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 90% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 92% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 93% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 95% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 97% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 98% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 99% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having 100% sequence identity to SEQ ID NO: 4. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 5. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 5. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 5. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least -58- ^{Docket No. 421688-718021 (718WO1)} about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 6. A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 6. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 6. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 7. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 7. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 7. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 8. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 8. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 8. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 9. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 9. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 9. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least -59- ^{Docket No. 421688-718021 (718WO1)} about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 10. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 10. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 10. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 11. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 11. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 11. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 12. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 12. A CNS- enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 12. A CNS- enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 13. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 13. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, -60- ^{Docket No. 421688-718021 (718WO1)} 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 13. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 14. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 14. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 14. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 15. A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 15. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 15. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 16. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 16. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 16. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 17. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at -61- ^{Docket No. 421688-718021 (718WO1)} least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 17. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 17. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 18. A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 18. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 18. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 70% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 72% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 75% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 78% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 80% sequence identity to SEQ ID NO: 19. A CNS- enhancer may comprise a sequence having at least about 85% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 87% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 90% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 92% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 93% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 95% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 97% sequence identity to SEQ ID NO: 19. A CNS- enhancer may comprise a sequence having at least about 98% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 99% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 100% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least -62- ^{Docket No. 421688-718021 (718WO1)} 70% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 72% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 75% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 78% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 80% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 85% sequence identity to SEQ ID NO: 19. A CNS- enhancer may comprise a sequence having at least 87% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 90% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 92% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 93% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 95% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 97% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 98% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least 99% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 70% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 72% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 75% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 78% sequence identity to SEQ ID NO: 19. A CNS- enhancer may comprise a sequence having about 80% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 85% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 87% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 90% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 92% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 93% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 95% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 97% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 98% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 99% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having about 100% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 70% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 72% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 75% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 78% sequence identity to SEQ ID NO: 19. A CNS-enhancer may -63- ^{Docket No. 421688-718021 (718WO1)} comprise a sequence having 80% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 85% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 87% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 90% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 92% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 93% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 95% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 97% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 98% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 99% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having 100% sequence identity to SEQ ID NO: 19. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 20. A CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 20. A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 20. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 360. In some embodiments, a CNS-enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 360. In some embodiments, a CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 360. [0192] In some embodiments, the reverse complement of a CNS-enhancer (e.g., a reverse complement of any of SEQ ID NO: 1 – SEQ ID NO: 40, SEQ ID NO: 237 – SEQ ID NO: 286, or SEQ ID NO: 360) may also be active as a CNS-enhancer. A CNS-enhancer of any of SEQ ID NO: 1 – SEQ ID NO: 40 or SEQ ID NO: 360 may have a reverse complement sequence of any -64- ^{Docket No. 421688-718021 (718WO1)} of SEQ ID NO 41 – SEQ ID NO: 80 or SEQ ID NO: 385, respectively, that is also active as a CNS-enhancer. A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 1 (e.g., SEQ ID NO: 41). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 1 (e.g., SEQ ID NO: 41). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 1 (e.g., SEQ ID NO: 41). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 2 (e.g., SEQ ID NO: 42). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 2 (e.g., SEQ ID NO: 42). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 2 (e.g., SEQ ID NO: 42). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 3 (e.g., SEQ ID NO: 43). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 3 (e.g., SEQ ID NO: 43). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 3 (e.g., SEQ ID NO: 43). A CNS-enhancer may comprise a sequence having at least about 70%, at least about -65- ^{Docket No. 421688-718021 (718WO1)} 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 4 (e.g., SEQ ID NO: 44). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 4 (e.g., SEQ ID NO: 44). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 4 (e.g., SEQ ID NO: 44). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 5 (e.g., SEQ ID NO: 45). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 5 (e.g., SEQ ID NO: 45). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 5 (e.g., SEQ ID NO: 45). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 6 (e.g., SEQ ID NO: 46). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 6 (e.g., SEQ ID NO: 46). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 6 (e.g., SEQ ID NO: 46). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at -66- ^{Docket No. 421688-718021 (718WO1)} least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 7 (e.g., SEQ ID NO: 47). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 7 (e.g., SEQ ID NO: 47). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 7 (e.g., SEQ ID NO: 47). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 8 (e.g., SEQ ID NO: 48). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 8 (e.g., SEQ ID NO: 48). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 8 (e.g., SEQ ID NO: 48). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 9 (e.g., SEQ ID NO: 49). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 9 (e.g., SEQ ID NO: 49). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 9 (e.g., SEQ ID NO: 49). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 10 (e.g., SEQ ID NO: 50). A CNS- -67- ^{Docket No. 421688-718021 (718WO1)} enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 10 (e.g., SEQ ID NO: 50). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 10 (e.g., SEQ ID NO: 50). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 11 (e.g., SEQ ID NO: 51). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 11 (e.g., SEQ ID NO: 51). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 11 (e.g., SEQ ID NO: 51). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 12 (e.g., SEQ ID NO: 52). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 12 (e.g., SEQ ID NO: 52). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 12 (e.g., SEQ ID NO: 52). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 13 (e.g., SEQ ID NO: 53). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at -68- ^{Docket No. 421688-718021 (718WO1)} least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 13 (e.g., SEQ ID NO: 53). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 13 (e.g., SEQ ID NO: 53). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 14 (e.g., SEQ ID NO: 54). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 14 (e.g., SEQ ID NO: 54). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 14 (e.g., SEQ ID NO: 54). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 15 (e.g., SEQ ID NO: 55). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 15 (e.g., SEQ ID NO: 55). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 15 (e.g., SEQ ID NO: 55). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 16 (e.g., SEQ ID NO: 56). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 16 (e.g., SEQ ID NO: 56). A CNS-enhancer may comprise a -69- ^{Docket No. 421688-718021 (718WO1)} sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 16 (e.g., SEQ ID NO: 56). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 17 (e.g., SEQ ID NO: 57). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 17 (e.g., SEQ ID NO: 57). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 17 (e.g., SEQ ID NO: 57). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 18 (e.g., SEQ ID NO: 58). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 18 (e.g., SEQ ID NO: 58). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 18 (e.g., SEQ ID NO: 58). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 19 (e.g., SEQ ID NO: 59). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 19 (e.g., SEQ ID NO: 59). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 19 (e.g., SEQ -70- ^{Docket No. 421688-718021 (718WO1)} ID NO: 59). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 20 (e.g., SEQ ID NO: 60). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 20 (e.g., SEQ ID NO: 60). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 20 (e.g., SEQ ID NO: 60). A CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 360 (e.g., SEQ ID NO: 385). A CNS- enhancer may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 360 (e.g., SEQ ID NO: 385). A CNS-enhancer may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 360 (e.g., SEQ ID NO: 385). [0193] A CNS-enhancer may comprise a duplication of an enhancer sequence. In some embodiments, a CNS-enhancer may comprise a duplication of any of SEQ ID NO: 1 – SEQ ID NO: 40 or SEQ ID NO: 41 – SEQ ID NO: 80 (e.g., any of SEQ ID NO: 267 – SEQ ID NO: 286). In some embodiments, a CNS-enhancer may comprise a duplication of SEQ ID NO: 360 or SEQ ID NO: 385. A CNS-enhancer may comprise two copies of SEQ ID NO: 1. A CNS- enhancer may comprise two copies of SEQ ID NO: 2. A CNS-enhancer may comprise two copies of SEQ ID NO: 3. A CNS-enhancer may comprise two copies of SEQ ID NO: 4. A CNS- enhancer may comprise two copies of SEQ ID NO: 5. A CNS-enhancer may comprise two copies of SEQ ID NO: 6. A CNS-enhancer may comprise two copies of SEQ ID NO: 7. A CNS- enhancer may comprise two copies of SEQ ID NO: 8. A CNS-enhancer may comprise two copies of SEQ ID NO: 9. A CNS-enhancer may comprise two copies of SEQ ID NO: 10. A CNS-enhancer may comprise two copies of SEQ ID NO: 11. A CNS-enhancer may comprise -71- ^{Docket No. 421688-718021 (718WO1)} two copies of SEQ ID NO: 12. A CNS-enhancer may comprise two copies of SEQ ID NO: 13. A CNS-enhancer may comprise two copies of SEQ ID NO: 14. A CNS-enhancer may comprise two copies of SEQ ID NO: 15. A CNS-enhancer may comprise two copies of SEQ ID NO: 16. A CNS-enhancer may comprise two copies of SEQ ID NO: 17. A CNS-enhancer may comprise two copies of SEQ ID NO: 18. A CNS-enhancer may comprise two copies of SEQ ID NO: 19. A CNS-enhancer may comprise two copies of SEQ ID NO: 20. A CNS-enhancer may comprise two copies of SEQ ID NO: 360. [0194] In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 267. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 268. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 269. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 270. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 271. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 272. In some embodiments, a CNS-enhancer may comprise a sequence having at least about -72- ^{Docket No. 421688-718021 (718WO1)} 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 273. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 274. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 275. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 276. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 277. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 278. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 279. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: -73- ^{Docket No. 421688-718021 (718WO1)} 280. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 281. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 282. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 283. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 284. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 285. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 286. [0195] A CNS-enhancer may comprise a triplication of an enhancer sequence. In some embodiments, a CNS-enhancer may comprise a triplication of any of SEQ ID NO: 1 – SEQ ID NO: 40, SEQ ID NO: 41 – SEQ ID NO: 80, SEQ ID NO: 360, or SEQ ID NO: 385. A CNS- enhancer may comprise three copies of SEQ ID NO: 1. A CNS-enhancer may comprise three copies of SEQ ID NO: 2. A CNS-enhancer may comprise two copies of SEQ ID NO: 3. A CNS- enhancer may comprise three copies of SEQ ID NO: 4. A CNS-enhancer may comprise three copies of SEQ ID NO: 5. A CNS-enhancer may comprise three copies of SEQ ID NO: 6. A -74- ^{Docket No. 421688-718021 (718WO1)} CNS-enhancer may comprise three copies of SEQ ID NO: 7. A CNS-enhancer may comprise two copies of SEQ ID NO: 8. A CNS-enhancer may comprise three copies of SEQ ID NO: 9. A CNS-enhancer may comprise three copies of SEQ ID NO: 10. A CNS-enhancer may comprise three copies of SEQ ID NO: 11. A CNS-enhancer may comprise three copies of SEQ ID NO: 12. A CNS-enhancer may comprise three copies of SEQ ID NO: 13. A CNS-enhancer may comprise three copies of SEQ ID NO: 14. A CNS-enhancer may comprise three copies of SEQ ID NO: 15. A CNS-enhancer may comprise three copies of SEQ ID NO: 16. A CNS-enhancer may comprise three copies of SEQ ID NO: 17. A CNS-enhancer may comprise three copies of SEQ ID NO: 18. A CNS-enhancer may comprise three copies of SEQ ID NO: 19. A CNS-enhancer may comprise three copies of SEQ ID NO: 20. A CNS-enhancer may comprise three copies of SEQ ID NO: 360. [0196] A CNS-enhancer may comprise a combination of enhancer sequences. In some embodiments, a CNS-enhancer may comprise two or more of SEQ ID NO: 1 – SEQ ID NO: 40 or SEQ ID NO: 41 – SEQ ID NO: 80 (e.g., any of SEQ ID NO: 237 – SEQ ID NO: 266). A CNS-enhancer may comprise a copy of SEQ ID NO: 13 and a copy of SEQ ID NO: 4. A CNS- enhancer may comprise a copy of SEQ ID NO: 13 and a copy of SEQ ID NO: 14. A CNS- enhancer may comprise a copy of SEQ ID NO: 13 and a copy of SEQ ID NO: 15. A CNS- enhancer may comprise a copy of SEQ ID NO: 13 and a copy of SEQ ID NO: 19. A CNS- enhancer may comprise a copy of SEQ ID NO: 13 and a copy of SEQ ID NO: 20. A CNS- enhancer may comprise a copy of SEQ ID NO: 4 and a copy of SEQ ID NO: 14. A CNS- enhancer may comprise a copy of SEQ ID NO: 4 and a copy of SEQ ID NO: 15. A CNS- enhancer may comprise a copy of SEQ ID NO: 4 and a copy of SEQ ID NO: 19. A CNS- enhancer may comprise a copy of SEQ ID NO: 4 and a copy of SEQ ID NO: 20. A CNS- enhancer may comprise a copy of SEQ ID NO: 14 and a copy of SEQ ID NO: 15. A CNS- enhancer may comprise a copy of SEQ ID NO: 14 and a copy of SEQ ID NO: 19. A CNS- enhancer may comprise a copy of SEQ ID NO: 14 and a copy of SEQ ID NO: 20. A CNS- enhancer may comprise a copy of SEQ ID NO: 15 and a copy of SEQ ID NO: 19. A CNS- enhancer may comprise a copy of SEQ ID NO: 15 and a copy of SEQ ID NO: 20. A CNS- enhancer may comprise a copy of SEQ ID NO: 19 and a copy of SEQ ID NO: 20. In some embodiments, a CNS-enhancer may comprise two or more of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 360, or SEQ ID NO: 385. [0197] In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at -75- ^{Docket No. 421688-718021 (718WO1)} least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 237. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 238. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 239. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 240. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 241. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 242. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 243. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 244. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least -76- ^{Docket No. 421688-718021 (718WO1)} about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 245. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 246. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 247. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 248. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 249. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 250. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 251. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 252. In some embodiments, a CNS-enhancer may comprise a sequence having at least about -77- ^{Docket No. 421688-718021 (718WO1)} 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 253. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 254. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 255. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 256. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 257. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 258. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 259. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: -78- ^{Docket No. 421688-718021 (718WO1)} 260. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 261. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 262. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 263. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 264. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 265. In some embodiments, a CNS-enhancer may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 266. Liver-Enhancers [0198] The enhancers may be tissue specific enhancers (e.g., liver enhancers). A tissue specific enhancer may result in enhanced, repressed, or altered transcription of a downstream sequence (e.g., a transgene sequence encoded by the polynucleotide) in a specific cell type of a tissue or tissue type (e.g., liver cells or liver tissue). The tissue specific enhancers and core promoters described herein may be appended to a payload sequence (e.g., a transgene encoding a therapeutic protein) to promote tissue-specific transcription of the payload sequence. In some -79- ^{Docket No. 421688-718021 (718WO1)} embodiments, enhancers may be combined or used in combination with other enhancers to tune transcriptional levels of the payload sequence. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more enhancers may be combined to tune transcriptional levels of the payload sequence. The combined 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more enhancers may all be the same enhancer, different enhancers, or any combination thereof. In some embodiments, an enhancer (e.g., an enhancer of SEQ ID NO: 362) may be duplicated or repeated 2, 3, 4, or more times. [0199] In some embodiments, a tissue-specific enhancer may be a liver-enhancer sequence. In some embodiments, the liver-enhancer has a sequence of: TCTTACCAGTGTGTGGCCTTGGGTCCTGGAAAAGTCCTTCATTTAGAGCAGAAACCA AAGCTTCAGCTTTGCAGCCCAGAACCTTCAGCAAATATTTGCTATTCCAAAGTATGAT CCCCTGTGGGACGGTTACTGATTAACATCCTGCTTGTGATGGTGGAGTTTCTGGA (SEQ ID NO: 362). In some embodiments the liver-enhancer has a reverse complement sequence of: TCCAGAAACTCCACCATCACAAGCAGGATGTTAATCAGTAACCGTCCCACAGGGGAT CATACTTTGGAATAGCAAATATTTGCTGAAGGTTCTGGGCTGCAAAGCTGAAGCTTTG GTTTCTGCTCTAAATGAAGGACTTTTCCAGGACCCAAGGCCACACACTGGTAAGA (SEQ ID NO: 386). [0200] A polynucleotide encoding a liver-enhancer sequence of the presence disclosure may enhance transcriptional activity of a polynucleotide encoding a payload sequence, wherein the polynucleotide encoding the payload is under transcriptional control of a promoter comprising the polynucleotide encoding the liver-enhancer sequence. An increase in cell transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target cell type relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences. A liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote cell transcription activity in a target liver-cell type at a rate that is higher than the rate of cell transcription activity in a non-target cell type. In some embodiments, a liver-enhancer sequence (SEQ ID NO: 362 or SEQ ID NO: 386) may promote cell transcription activity in a target liver- cell type at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20- fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity in a non-target cell type. In some embodiments, a liver-enhancer sequence (SEQ ID NO: 362 or SEQ ID NO: 386) may promote cell transcription activity at a rate that is at least about 1- -80- ^{Docket No. 421688-718021 (718WO1)} fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity of a different enhancer sequence/promoter sequences. An increase in tissue transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target tissue relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences. A liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote tissue transcription activity in a target liver tissue at a rate that is higher than the rate of tissue transcription activity in a non-target tissue. In some embodiments, a liver-enhancer sequence (SEQ ID NO: 362 or SEQ ID NO: 386) may promote tissue transcription activity in a target liver tissue at a rate that is at least about 1- fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of tissue transcription activity in a non-target tissue. In some embodiments, a liver-enhancer sequence (SEQ ID NO: 362 or SEQ ID NO: 386) may promote tissue transcription activity at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10- fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of tissue transcription activity of a different enhancer sequence/promoter sequences. [0201] A liver-enhancer sequence of the presence disclosure may enhance transcription specificity in liver cells (e.g., hepatic cells) or tissue of a payload sequence under transcriptional control of the liver-enhancer sequence in a polynucleotide. An increase in cell transcriptional specificity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) of cell transcription activity in a target cell type relative to one or more non-target cell types. A liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote cell transcription specificity in a target liver-cell type over a non-target cell, in which the rate of cell transcription activity is higher in the target liver-cell type than the rate of cell transcription activity in a non-target cell type. In some embodiments, a liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote cell transcription specificity in a target liver-cell type over a non-target cell, in which the rate of cell transcription activity in a target liver-cell -81- ^{Docket No. 421688-718021 (718WO1)} type at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity in a non-target cell type. An increase in tissue transcriptional specificity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) of tissue transcription activity in a target tissue relative to one or more non-target tissue. A liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote tissue transcription specificity in a target liver tissue over a non-target tissue, in which the rate of tissue transcription activity is higher in the target liver tissue than the rate of tissue transcription activity in a non-target tissue. In some embodiments, a liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote tissue transcription specificity in a target liver tissue over a non-target tissue, in which the rate of tissue transcription activity in a target liver tissue at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of tissue transcription activity in a non-target tissue. [0202] The liver-enhancer sequences of the presence disclosure enhance transcription activity and transcription specificity in liver cells or tissue of a payload sequence under transcriptional control of the liver-enhancer sequence. An increase in cell transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target cell type relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences and an increase in cell transcriptional specificity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) of cell transcription activity for a target cell type relative to one or more non-target cell types. A liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote cell transcription specificity in a target liver-cell type over a non-target cell, in which the rate of cell transcription activity is higher in the target liver-cell type than the rate of cell transcription activity in a non-target cell type. In some embodiments, a liver- enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote cell transcription specificity in a target liver-cell type over a non-target cell, in which the rate of cell transcription activity in a target liver-cell type at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10- -82- ^{Docket No. 421688-718021 (718WO1)} fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity in a non-target cell type. In some embodiments, a liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote cell transcription activity at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30- fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of cell transcription activity when paired with a non-liver enhancer/promoter (e.g., enhancer/core promoter) sequence). An increase in tissue transcriptional activity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) for a target tissue relative to other enhancer/promoter (e.g., enhancer/core promoter) sequences and an increase in tissue transcriptional specificity may be expressed as fold activation, fold change (FC), or a log of the fold change (logFC) of tissue transcription activity for a target tissue relative to one or more non-target tissues. A liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote tissue transcription specificity in a target liver tissue over a non-target tissue, in which the rate of tissue transcription activity is higher in the target liver tissue than the rate of tissue transcription activity in a non-target tissue. In some embodiments, a liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote tissue transcription specificity in a target liver tissue over a non-target tissue, in which the rate of tissue transcription activity in a target liver tissue at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4- fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of tissue transcription activity in a non-target tissue. In some embodiments, a liver-enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) may promote tissue transcription activity at a rate that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50- fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher than the rate of tissue transcription activity when paired with a non-liver enhancer/promoter (e.g., enhancer/core promoter) sequence). -83- ^{Docket No. 421688-718021 (718WO1)} [0203] In some embodiments, a liver-enhancer sequence may comprise a sequence of any one of SEQ ID NO: 362 or SEQ ID NO: 386. In some embodiments, a liver-enhancer sequence may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to any of SEQ ID NO: 362 or SEQ ID NO: 386. In some embodiments, a liver-enhancer sequence may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to any of SEQ ID NO: 362 or SEQ ID NO: 386. In some embodiments, a liver-enhancer sequence may comprise a sequence having about 70%, about 72%, about 75%, about 78%, about 80%, about 82%, about 85%, about 87%, about 90%, about 92%, about 93%, about 95%, about 97%, about 98%, about 99%, or about 100% sequence identity to any of SEQ ID NO: 362 or SEQ ID NO: 386. In some embodiments, a liver-enhancer sequence may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to any of SEQ ID NO: 362 or SEQ ID NO: 386. [0204] A liver-enhancer sequence may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 70% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 72% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 75% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 78% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 80% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 85% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 87% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 90% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 92% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 93% sequence identity to SEQ ID NO: 362. A liver- enhancer may comprise a sequence having at least about 95% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 97% sequence identity to -84- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 98% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 99% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least about 100% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 70% sequence identity to SEQ ID NO: 362. A liver- enhancer may comprise a sequence having at least 72% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 75% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 78% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 80% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 85% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 87% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 90% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 92% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 93% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 95% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 97% sequence identity to SEQ ID NO: 362. A liver- enhancer may comprise a sequence having at least 98% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having at least 99% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 70% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 72% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 75% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 78% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 80% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 85% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 87% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 90% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 92% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 93% sequence identity to SEQ ID NO: 362. A liver- enhancer may comprise a sequence having about 95% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 97% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 98% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 99% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having about 100% sequence -85- ^{Docket No. 421688-718021 (718WO1)} identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 70% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 72% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 75% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 78% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 80% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 85% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 87% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 90% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 92% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 93% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 95% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 97% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 98% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 99% sequence identity to SEQ ID NO: 362. A liver-enhancer may comprise a sequence having 100% sequence identity to SEQ ID NO: 362. [0205] In some embodiments, the reverse complement of a liver-enhancer sequence may also be active as a liver-enhancer sequence. A liver-enhancer sequence of SEQ ID NO: 362 may have a reverse complement sequence of SEQ ID NO: 386, that is also active as a liver-enhancer sequence. A liver-enhancer sequence may comprise a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 362 (e.g., SEQ ID NO: 386). In some embodiments, a liver-enhancer sequence may comprise a sequence having at least 70%, at least 72%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 87%, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 362 (e.g., SEQ ID NO: 386). In some embodiments, a liver-enhancer sequence may comprise a sequence having about 70%, about 72%, about 75%, about 78%, about 80%, about 82%, about 85%, about 87%, about 90%, about 92%, about 93%, about 95%, about 97%, about 98%, about 99%, or about 100% sequence identity to a reverse complement of SEQ ID NO: 362 (e.g., SEQ ID NO: 386). In some embodiments, a liver-enhancer sequence may comprise a sequence having 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, 99%, or 100% sequence identity to a reverse complement of SEQ ID NO: 362 (e.g., SEQ ID NO: 386). -86- ^{Docket No. 421688-718021 (718WO1)} Core Promoters [0206] The promoter of a polynucleotide may comprise a core promoter that facilitates recruitment of transcription machinery and initiation of transcription. In some embodiments, the core promoter may be positioned downstream (i.e., 3’) of the enhancer. In some embodiments, the core promoter may be positioned upstream (i.e., 5’) of a payload (e.g., a transgene). The core promoter may recruit polymerase or proteins that bind to polymerases to initiate transcription of a sequence downstream of the core promoter. For example, the core promoter may recruit an RNA polymerase (e.g., RNA polymerase II) or a TATA binding protein (TBP) that recruits an RNA polymerase. For example, the core promoter may bind to general transcription factors (GTFs) which recruit RNA polymerase II (Pol II) to initiate transcription. The ability of the core promoter to recruit transcription machinery (e.g., an RNA polymerase) or the affinity of the core promoter for the transcription machinery may affect transcription levels. In some embodiments, the core promoter may be altered to tune transcription levels by altering recruitment of and/or affinity for transcription machinery. [0207] A core promoter may be an endogenous promoter sequence. A core promoter sequence may be a synthetic promoter sequence. In some embodiments, the core promoter is a minimal synthetic core promoter. Core promoters may be selected or engineered for one or more desired transcriptional properties, such as transcription level, cell type specificity, or cell genotype specificity. For example, a core promoter may be selected to promote transcription in neurons and little to no transcription in non-neuronal cell types. Engineering a core promoter may comprise screening variants of a core promoter for transcription level, cell type specificity, and/or cell genotype specificity. [0208] In some embodiments, a core promoter may comprise a TATA box (e.g., TATAAA), an RNA polymerase binding sequence, a B recognition element (BRE, e.g., G/C,G/C,G/A,CGCC), a CCAAT box or CAT box (e.g., GGCCAATCT), or a Pribnow box (e.g., TATAAT). Examples of core promoters are provided in TABLE 2. TABLE 2 – Exemplary Core Promoters SEQ ID NO Sequence SEQ ID NO: 81 GTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTT AGTGAACCGTCAGATC SEQ ID NO: 82 CAACAAAATGTCGTAACAAGGGCGGTAGGCGTGTACGGTGGGA GGTCTATATAAGCAGAGCTCGTTTAGTGAACCG SEQ ID NO: 83 TGCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCG CCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCC CCATCGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCG -87- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO Sequence CCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTT GGAGGCCTAGGCTTTTGCAAAAAGCTT SEQ ID NO: 84 TTCGCATATTAAGGTGACGCGTGTGGCCTCGAACACCGAGCGA CCCTGCAGCGACCCGCTTAA SEQ ID NO: 85 GGGGGGCTATAAAAGGGGGTGGGGGCGTTCGTCCTCACTCT SEQ ID NO: 86 CTGACAAATTCAGTATAAAAGCTTGGGGCTGGGGCCGAGCACT GGGGACTTTGAGGGTGGCCAGGCCAGCGTAGGAGGCCAGCGTA GGATCCTGCTGGGAGCGGGGAACTGAGGGAAGCGACGCCGAG AAAGCAGGCGTACCACGGAGGGAGAGAAAAGCTCCGGAAGCC CAGCAGCG SEQ ID NO: 87 TCTAGAGGGTATATAATGGGGGCCA SEQ ID NO: 88 TATAAAAG SEQ ID NO: 89 TATAAT SEQ ID NO: 90 G/C,G/C,G/A,CGCC SEQ ID NO: 91 GGCCAATCT SEQ ID NO: 92 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTTTTGG AGGGCCTCCCTTTAGCGTGTGAGGTGCTGTAATTCCCCC SEQ ID NO: 93 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG CAAGATGGCGGTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 94 GGGTTATATAAGGGCGCCGCGCGGGTGATTACTGTCAGTCTTTT GG SEQ ID NO: 95 TAGAGGGTATATAAAGGAAGCTCGACTTCCAGCTTGGCATTCC GG SEQ ID NO: 96 TAGAGGGTATATAATGGAAGCTCGACTTCCAGCTTGGCAATCC GG SEQ ID NO: 97 GTACTTATATAAGGGGGTGGGGGCGCGTTCGTCCTCAGTCGCG ATCGAACACTCGAGCCGAGCAGACGTGCCTACGGACCG SEQ ID NO: 98 GGGGTATAAAAGCCCCCGGCGCGATTACTGACATTCTTTTGG SEQ ID NO: 99 GGGTACGCCCCTTTTTATGCGCGTGATTACTGCACAGGAATTGG SEQ ID NO: 100 TCTAGAGGGTATATAATGGGGGCCACTAGTCTACTACCAGAAA G SEQ ID NO: 101 GGGTTATATAAGGGCGCCTGGAAGGCGATTTCAGTCTTG SEQ ID NO: 102 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGG GAGAAGCGGGTGAAAGCAGGGCGGGGCTATAACTCGGCG SEQ ID NO: 103 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG CAAGATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 104 GGGTTATATAAGGGCGCCGCGCGTGATTACTGACATTCTTTTGG SEQ ID NO: 105 GGGGTATAAAAGGCGGGGTGGAATTGGCGATTTCAGTCTGGAA GGGGGGTAGGGTGCGTGGAAGCAGTTATAAAACGAAC -88- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO Sequence SEQ ID NO: 106 TAGAGGGTATATAAGGGAAGCTCGACTTCCAGCTTGGCACTCC GG SEQ ID NO: 107 GGGGTATAAAAGGCGGGGTGGAAGGCGATTTCAGTCTTG SEQ ID NO: 108 AGGACCGGATCAACTAGGTCTATATAAGCAGAGCTCGTTTAGT GAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACC TCCATAGAATTGGTACCGAGCTCG SEQ ID NO: 109 GGGGTATAAAAGGCGGGGTGGAATTGGCGATTTCAGTCTGGGA CGAGCGCGTGGGGGGTGACGGTGGCTGATTATCACGG SEQ ID NO: 110 GGGGTATAAAAGGCGGGGTGGAATTGGCGATTTCAGTCTGGAG GGCCTCCCTTTAGCGTGTGAGGTGCTGTAATTCCCCC SEQ ID NO: 111 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG GGACGAGCGCGTGGGGGGTGACGGTGGCTGATTATCACGG SEQ ID NO: 112 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG GAGGGCCTCCCTTTAGCGTGTGAGGTGCTGTAATTCCCCC SEQ ID NO: 113 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGG GACGAGCGCGTGGGGGGTGACGGTGGCTGATTATCACGG SEQ ID NO: 114 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGG AGGGCCTCCCTTTAGCGTGTGAGGTGCTGTAATTCCCCC SEQ ID NO: 115 GGGGTATAAAAGGCTGACCGCAGATGATTAAATCAGTCTTTTG G SEQ ID NO: 116 GGGGTATAAAAGCCGGGGAGGAACAGATAAGATCAGTCTTTTG G SEQ ID NO: 117 GGGGTATAAAAGGCGGGGGGGTTGTGCAATCGTCAGTCTGTTG G SEQ ID NO: 118 GGGGTATAAAAGGCTGCTTCCACAAGATTAGCTCAGTCTTTTGG SEQ ID NO: 119 GGGGTATAAAAGGCGGGGAAGTCCAAGGTCCATCAGTCTGTTG G SEQ ID NO: 120 GGGGTATAAAAGGCTGCTTCCACAAGATTAGCTCAGTCTGTTGG SEQ ID NO: 121 GGGGTATAAAAGCCCCCGAAGTCCAAGGTCCATCAGTCTGTTG G SEQ ID NO: 122 GGGGTATAAAAGCCTGACCGCAGATGATTAAATCAGTCTGTTG G SEQ ID NO: 123 GGGGTATAAAAGGCGGGGAAGTCCAAGGTCCATCAGTCTTTTG G SEQ ID NO: 124 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTTTTG CAAGATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 125 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCATTGACTTGC AAGATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 126 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCATTGACTTGC AAGATGGCGGTGGTGCGTGGAAGCAGTTATAAAACGAAC -89- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO Sequence SEQ ID NO: 127 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCATTGACTTGC AAGATGGCGGCTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 128 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCATTGACTTGC AAGATGGCGGTTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 129 GGGGTATAAAAGGCGGGGTGGAATTGGCGATTTCAGTCTTGAA CAAGATGGCGGCGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 130 GGGGTATAAAAGGCGGGGTGGAATTGGCGATTTCAGTCTTGAA CAAGATGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 131 GGGGTATAAAAGGCGGGGTGGAATTGGCGATTTCAGTCTTGAA GCCGCCATCTTGGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 132 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTTTTGC AAGATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 133 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTTTTGC AAAATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 134 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTTTTGC AAGATGGCGGTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 135 GGGGTATAAAAGGCGGGGTGGAATTGGCGATTTCAGTCTGGAA CAAGATGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 136 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTTTTG CAAAATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 137 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTTTTGA AATATGGCGCTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 138 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTTTTGA GCGCCATATTTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 139 GGGGTATAAAAGGCGGGGTGGAATTGGCGATTTCATTGACGAA ACCGCCATCTTGGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 140 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTTTTGC AAGATGGCGGCTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 141 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTTTTGC AAAATGGCGGCTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 142 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTTTTG AAATATGGCGCTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 143 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG CAAAATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 144 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG AAATATGGCGCTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 145 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG ACCGCCATCTTGGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 146 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG CAAGATGGCGGCTGCAGTCCCAGTTGCGATAGAAACCCCC -90- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO Sequence SEQ ID NO: 147 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG CAAAATGGCGGCTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 148 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG CAAGATGGCGGTTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 149 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGC AAGATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 150 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGC AAAATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 151 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGC AAGATGGCGGTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 152 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGA AATATGGCGCTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 153 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGG CCGCCATCTTGGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 154 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGC AAGATGGCGGCTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 155 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGC AAGATGGCGGTTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 156 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGA AATATGGCGCTTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 157 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGA CCGCCATCTTGTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 158 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTTTTG AGCGCCATATTTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 159 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTTTTG CAAGATGGCGGCTGCAGTCCCAGTTGCGATAGAAACCCCC SEQ ID NO: 160 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCATTGACTTG CAAGATGGCGGCGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 161 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCATTGACTTG CAAGATGGCGGTGGTGCGTGGAAGCAGTTATAAAACGAAC SEQ ID NO: 162 GGGGTATAAAAGGCGGGGGCGCGGGTGATTACTGTCAGTCTTT TGG SEQ ID NO: 163 GGGGTATAAAAGGCGGGGGCGCGGGTGATTACTGTCAGTCTCT TGG SEQ ID NO: 164 GGGGTATAAAAGGCGGGGTGGAAGGTTGGCGATTTCAGTCTTG SEQ ID NO: 165 GGGGTATAAAAGCCCCCGTGGAAGGTTGGCGATTTCAGTCTTG SEQ ID NO: 166 GGGTTATATAAGGGCGCCTGGAAGGTTGGCGATTTCAGTCTTG SEQ ID NO: 167 GGGGTATAAAAAGCGGGGGCGCGGGTGATTACTGTCAGTCTCT TGG SEQ ID NO: 168 GGGGTATAAAAGGCGGGGTGGAAGGTTGGCGATTTCAGTCTCG -91- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO Sequence SEQ ID NO: 169 GGGTTATATAAGGGCGCCTGGAAGGTTGGCGATTTCAGTCTCG SEQ ID NO: 170 GGGGTATAAAAGCCCCCGGCGCGGGTGATTACTGTCAGTCTCTT GG SEQ ID NO: 171 GGGGTATAAAAGGCGGGGTGGAAGGTTGGCGATTTCAGTCTGG SEQ ID NO: 172 GGGGTATAAAAAGCGGGGTGGAAGGTTGGCGATTTCAGTCTGG SEQ ID NO: 173 GGGTTATATAAGGGCGCCTGGAAGGTTGGCGATTTCAGTCTGG SEQ ID NO: 174 GGGGTATAAAAGGCGGGGTGGAAGGTTGGCGATTTCAGTAGTG SEQ ID NO: 175 GGGGTATAAAAAGCGGGGTGGAAGGTTGGCGATTTCAGTAGTG SEQ ID NO: 176 GGGGTATAAAAGCCCCCGTGGAAGGTTGGCGATTTCAGTAGTG SEQ ID NO: 177 GGGTTATATAAGGGCGCCTGGAAGGTTGGCGATTTCAGTAGTG SEQ ID NO: 178 GGGGTATAAAAGGCGGGGTGGAAGGTTGGCGATTACATTCTTG SEQ ID NO: 179 GGGTTATATAAGGGCGCCGCGCGGGTGATTACTGTCAGTCTCTT GG SEQ ID NO: 180 GGGGTATAAAAGGCGGGGTGGAAGGTTGGCGATTTCATATCCG SEQ ID NO: 181 GGGTTATATAAGGGCGCCTGGAAGGTTGGCGATTTCATATCCG SEQ ID NO: 182 GGGTTATATAAGGGCGCCTGGAAGGTTGGCGATTTCATTGACG SEQ ID NO: 183 GGGGTATAAAAGGCGGGGTGGAAGGTTGGCGATTTCACAAACG SEQ ID NO: 184 GGGGTATAAAAAGCGGGGTGGAAGGTTGGCGATTTCACAAACG SEQ ID NO: 185 GGGTTATATAAGGGCGCCTGGAAGGTTGGCGATTTCACAAACG SEQ ID NO: 186 GGGGTATAAAAGGCGGGGTGGAAGGTTGGCGATTCACAGGAA G SEQ ID NO: 187 GGGGTATAAAAAGCGGGGGCGCGGGTGATTACTGTCAGTCTGT TGG SEQ ID NO: 188 GGGGTATAAAAGCCCCCGGCGCGGGTGATTACTGTCAGTCTGTT GG SEQ ID NO: 189 GGGTTATATAAGGGCGCCGCGCGGGTGATTACTGTCAGTCTGTT GG SEQ ID NO: 190 GGGGTATAAAAGCCCCCGGCGCGGGTGATTACTGTCAGTCTTTT GG SEQ ID NO: 191 GGGGTATAAAAGGCGGGGGCGCGGGTGATTACTGTCAGTAGTT TGG SEQ ID NO: 192 GGGGTATAAAAGCCCCCGGCGCGGGTGATTACTGTCAGTAGTT TGG SEQ ID NO: 193 GGGTTATATAAGGGCGCCGCGCGGGTGATTACTGTCAGTAGTTT GG SEQ ID NO: 194 GGGGTATAAAAGGCGGGGGCGCGGGTGATTACTGACATTCTTT TGG -92- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO Sequence SEQ ID NO: 195 GGGGTATAAAAGCCCCCGGCGCGGGTGATTACTGACATTCTTTT GG SEQ ID NO: 196 GGGTTATATAAGGGCGCCGCGCGGGTGATTACTGACATTCTTTT GG SEQ ID NO: 197 GGGGTATAAAAGCCCCCGGCGCGGGTGATTACTGTCATATCCTT GG SEQ ID NO: 198 GGGTTATATAAGGGCGCCGCGCGGGTGATTACTGTCATATCCTT GG SEQ ID NO: 199 GGGTTATATAAGGGCGCCGCGCGGGTGATTACTGTCATTGACTT GG SEQ ID NO: 200 GGGGTATAAAAGCCCCCGGCGCGGGTGATTACTGTCACAAACT TGG SEQ ID NO: 201 GGGTTATATAAGGGCGCCGCGCGGGTGATTACTGTCACAAACT TGG SEQ ID NO: 202 GGGGTATAAAAGGCGGGGGCGCGATTACTGTCAGTCTTTTGG SEQ ID NO: 203 GGGGTATAAAAGGCGGGGTGGAAGGCGATTTCAGTCTCG SEQ ID NO: 204 GGGTTATATAAGGGCGCCTGGAAGGCGATTTCAGTCTCG SEQ ID NO: 205 GGGGTATAAAAGGCGGGGTGGAAGGCGATTTCAGTAGTG SEQ ID NO: 206 GGGTTATATAAGGGCGCCTGGAAGGCGATTTCAGTAGTG SEQ ID NO: 207 GGGGTATAAAAAGCGGGGTGGAAGGCGATTACATTCTTG SEQ ID NO: 208 GGGTTATATAAGGGCGCCGCGCGATTACTGTCAGTCTCTTGG SEQ ID NO: 209 GGGTTATATAAGGGCGCCTGGAAGGCGATTACATTCTTG SEQ ID NO: 210 GGGGTATAAAAGGCGGGGTGGAAGGCGATTCACAGGAAG SEQ ID NO: 211 GGGGTATAAAAAGCGGGGTGGAAGGCGATTCACAGGAAG SEQ ID NO: 212 GGGGTATAAAAGCCCCCGTGGAAGGCGATTCACAGGAAG SEQ ID NO: 213 GGGTTATATAAGGGCGCCGCGCGATTACTGTCAGTAGTTTGG SEQ ID NO: 214 GGGGTATAAAAGGCGGGGGCGCGATTACTGACATTCTTTTGG SEQ ID NO: 215 GGGGTATAAAAAGCGGGGGCGCGATTACTGACATTCTTTTGG SEQ ID NO: 216 GGGTTATATAAGGGCGCCGCGCGATTACTGACATTCTTTTGG SEQ ID NO: 217 GGGTTATATAAGGGCGCCGCGCGATTACTGTCAGTCTTTTGG SEQ ID NO: 218 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTTTTG G SEQ ID NO: 219 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTCTTG G SEQ ID NO: 220 GGGTTATATAAGGGCGCCTGGAATTGGCGATTTCAGTCTTG SEQ ID NO: 221 GGGTTATATAAGGGCGCCTGGAATTGGCGATTTCAGTCTCG SEQ ID NO: 222 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTCTTGG -93- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO Sequence SEQ ID NO: 223 GGGTTATATAAGGGCGCCTGGAATTGGCGATTTCAGTCTGG SEQ ID NO: 224 GGGTTATATAAGGGCGCCTGGAATTGGCGATTTCAGTAGTG SEQ ID NO: 225 GGGTTATATAAGGGCGCCGCGCGTGATTACTGTCAGTCTCTTGG SEQ ID NO: 226 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTCTGTTG G SEQ ID NO: 227 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTGTTGG SEQ ID NO: 228 GGGTTATATAAGGGCGCCGCGCGTGATTACTGTCAGTCTGTTGG SEQ ID NO: 229 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTCTTTTGG SEQ ID NO: 230 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCAGTAGTTTG G SEQ ID NO: 231 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGTCAGTAGTTTG G SEQ ID NO: 232 GGGTTATATAAGGGCGCCGCGCGTGATTACTGTCAGTAGTTTGG SEQ ID NO: 233 GGGGTATAAAAGCCCCCGGCGCGTGATTACTGACATTCTTTTGG SEQ ID NO: 234 GGGTTATATAAGGGCGCCGCGCGTGATTACTGTCAGTCTTTTGG SEQ ID NO: 235 GGGGTATAAAAGGCGGGGGCGCGTGATTACTGTCACAAACTTG G SEQ ID NO: 236 GGGTTATATAAGGGCGCCGCGCGTGATTACTGTCACAAACTTG G SEQ ID NO: 363 GGGGTATAAAAAACGTCGGCGCGGGTGATTACTGTCAGTCTTTT GG SEQ ID NO: 364 GGGGTATAAAAGGCTGGCGGGGACAGATAAGATCAGTCTTTTG G SEQ ID NO: 365 GGGGTATAAAAGCCGGGGAGGAACAGATAAGATCAGTCTGTTG G SEQ ID NO: 366 TAGATGGTATATAAGGGAGGCTCGACATCCAGTTGGGCAATCC GG [0209] In some embodiments, a core promoter may comprise a sequence of any of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366. In some embodiments, the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. In some embodiments, the core promoter may comprise a sequence of SEQ ID NO: 95. In some embodiments, the core promoter may comprise a sequence of SEQ ID NO: 363. In some embodiments, the core promoter may comprise a sequence of SEQ ID NO: 364. In some embodiments, the core promoter may comprise a sequence of SEQ ID NO: 365. In some embodiments, the core promoter may comprise a sequence of SEQ ID NO: 366. -94- ^{Docket No. 421688-718021 (718WO1)} [0210] In some embodiments, the core promoter may be cell type generic. A cell type generic core promoter may have low basal activity alone (e.g., low levels of transcriptional activation in the absence of an enhancer) or when paired with an enhancer in a transcriptionally inactive state (e.g., an enhancer in the absence of co-activators, cognate ligands and/or transcription factors that bind to the enhancer) and high activity (e.g., high levels of transcriptional activation) when paired with an enhancer in a transcriptionally active state (e.g., an enhancer in the presence of co-activators, cognate ligands and/or transcription factors that bind to the enhancer). For example, a cell type generic core promoter may have low transcriptional activation in the absence of an enhancer, independent of cell or tissue type. The cell type generic core promoter may have high transcriptional activation when paired with a cell or tissue type-specific enhancer in a cell or tissue type of interest (e.g., in the presence of, or at high levels of, transcription factors that bind to the transcription factor binding sequence of an enhancer). The cell type generic core promoter may have low transcriptional activation when paired with a cell or tissue type-specific enhancer not in a cell or tissue type of interest (e.g., in the absence of, or at low levels of, transcription factors that bind to the transcription factor binding sequence of an enhancer). In some embodiments, a core promoter may be engineered to have low basal transcriptional activation and high transcriptional activation when paired with a cell or tissue type-specific enhancer in a cell or tissue type of interest. The sequence of the core promoter may be varied or engineered to tune the transcription level, tissue specificity, and/or cell type specificity. In some embodiments, a core promoter may comprise an endogenous core promoter or an engineered version of an endogenous core promoter. Enhancer/Promoter Libraries and Methods of Screening [0211] Described herein are enhancer/promoter (e.g., enhancer/core promoter) libraries for high- throughput screening for tissue type- or cell type-specific transcription. These libraries may be screened, for example using high-throughput assays, for desired characteristics such as tissue type-specific or cell type-specific regulation of transcription of a payload (e.g., a transgene). An enhancer/promoter (e.g., enhancer/core promoter) library may be compiled based on functional genomic data to generate a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) library comprising candidate enhancers expected to promote transcription in the tissue type of interest. For example, the enhancer/promoter (e.g., enhancer/core promoter) library may be a CNS-specific enhancer/promoter (e.g., enhancer/core promoter) library comprising enhancer candidates expected to promote transcription in excitatory neurons when paired with a core promoter. In another example, the enhancer/promoter library may be a liver-specific enhancer/promoter (e.g., enhancer/core promoter) library comprising enhancer sequence -95- ^{Docket No. 421688-718021 (718WO1)} candidates expected to promote transcription in liver cells (e.g., hepatocytes, hepatoblasts, hepatic stellate cells, Kupffer cells, or liver sinusoidal endothelial cells) when paired with a core promoter. [0212] Enhancers used in the tissue-specific enhancer/promoter (e.g., enhancer/core promoter) library may be compiled from candidate region sequences identified based on functional genomic data, such as tissue-specific chromatin accessibility, epigenetic markers such as DNA methylation or histone modification (e.g., lysine methylation, lysine acetylation, glutamine serotonylation, arginine methylation, or arginine citrullination), proximity to a marker gene (e.g., a gene specifically expressed in the tissue of interest), cis-regulatory elements, sequence conservation across vertebrates, or combinations thereof. In some embodiments, a candidate enhancer included in a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) library may be selected from a genomic region that is highly accessible, indicative of increased transcription, in the tissue type of interest and less accessible in other tissue types. Alternatively, or in addition, a candidate enhancer included in a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) library may be selected from a genomic region that coincides with histone acetylation (e.g., acetylation of a lysine residue at N-terminal position 27 of a histone H3 protein) in the tissue type of interest. Alternatively, or in addition, a candidate enhancer included in a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) library may be selected from a genomic region in proximity (e.g., within about 100 kilobases) to a gene specifically expressed in the tissue of interest (e.g., a neuronal marker gene selectively expressed in neurons, a hepatic marker gene selectively expressed in liver cells, or a kidney marker gene selectively expressed in kidneys). [0213] Functional genomic data may be obtained from a database or collected using a range of biochemical techniques. For example, functional genomic data comprising tissue-specific DNase I hypersensitive sites, tissue-specific gene expression, or both may be obtained from a database. In another example, functional genomic data comprising presence of cis-regulatory elements (CCREs) may be obtained from a database. Alternatively or in addition, functional genomic data may be collected using biochemical techniques. For example, transposase-accessible chromatin with high-throughput sequencing (sci-ATAC-seq), chromatin immunoprecipitation with massively parallel DNA (ChIP-seq), Dnase I hypersensitive sites sequencing (Dnase-seq), chromosome conformation capture (HiC), or a combination thereof may be used to assess chromatin accessibility for identifying enhancer candidates. [0214] A candidate enhancer may be selected from a candidate region based on coincidence with a peak in a functional genomic parameter (e.g., tissue-specific chromatin accessibility or -96- ^{Docket No. 421688-718021 (718WO1)} histone acetylation). The candidate enhancer may comprise a nucleotide sequence selected from the larger candidate region. In some embodiments, candidate enhancers of an enhancer library may comprise a length of no more than about 250 nucleotides. In some embodiments, a candidate enhancer may comprise a length of from about 100 nucleotides to about 250 nucleotides, from about 120 nucleotides to about 220 nucleotides, or from about 140 nucleotides to about 190 nucleotides. In some embodiments, a candidate enhancer may comprise a length of about 170 nucleotides. [0215] In some embodiments, an enhancer/promoter (e.g., enhancer/core promoter) library may comprise at least about 1,000, at least about 2,000, at least about 3,000, at least about 4,000, at least about 5,000, at least about 6,000, at least about 7,000, at least about 8,000, at least about 9,000, at least about 10,000, at least about 11,000, at least about 12,000, at least about 13,000, at least about 14,000, at least about 15,000, at least about 20,000, at least about 25,000, at least about 30,000 , at least about 40,000, or at least about 50,000 candidate enhancers. An enhancer/promoter (e.g., enhancer/core promoter) library may further comprise reference sequences or control sequences present in multiple libraries to facilitate cross-comparison of screening results. The library may be generated by synthesizing the candidate enhancers using any DNA synthesis method known in the art (e.g., phosphoramidite synthesis, phosphite triester synthesis, phosphotriester synthesis, phosphodiester synthesis, or H-phosphonate synthesis). [0216] An enhancer/promoter (e.g., enhancer/core promoter) library (e.g., a tissue-specific enhancer/promoter (e.g., enhancer/core promoter) library) may be screened using a high- throughput screening method. For example, the enhancer/promoter (e.g., enhancer/core promoter) library may be screened using a massively parallel reporter assay. Random barcodes may be added to each candidate enhancer in the enhancer/promoter (e.g., enhancer/core promoter) library. The resulting barcoded enhancers may be cloned into carrier plasmids. Next generation sequencing may be used to associate each enhancer candidate with its corresponding random barcode sequence. Barcoded enhancers may be cloned into a vector (e.g., a lentiviral transfer plasmid, an AAV plasmid, or a pGL4 plasmid) for expression and screening in a cell of interest. In some embodiments, the library may be screened in a cellular model of a tissue of interest. In some embodiments, the library may be screened in a tissue model of a tissue of interest. For example, a central nervous systems CNS-specific enhancer/promoter (e.g., enhancer/core promoter) library may be screened in a neuronal cell line. In another example, a central nervous systems CNS-specific enhancer/promoter (e.g., enhancer/core promoter) library may be screened in neuronal tissue. The cellular model may comprise a human cell line (e.g., Lund human mesencephalic (LUHMES) cells, HepG2 cells, H4 cells, or K562 cells). The -97- ^{Docket No. 421688-718021 (718WO1)} cellular model may comprise cultured mouse cells (e.g., mouse primary neurons). The cellular model may comprise induced pluripotent stem cells (e.g., human induced pluripotent stem cell derived neurons). In another example, a liver liver-specific enhancer/promoter (e.g., enhancer/core promoter) library may be screened in a liver cell line. In another example, a liver liver-specific enhancer/promoter (e.g., enhancer/core promoter) library may be screened in liver tissue. The cellular model may comprise a human cell line (e.g., Lund human mesencephalic (LUHMES) cells, HepG2 cells, H4 cells, or K562 cells). The tissue model may comprise isolated mouse tissues (e.g., mouse brain, liver, heart, kidney, gastrocnemius tissues). In some embodiments, the library is screened in various different cellular models of non-target tissues as controls. In some embodiments, the library is screened in various different tissue models of non- target tissues as controls. Expression levels from each candidate enhancer/promoter (e.g., enhancer/core promoter) may be assessed by quantifying levels of barcodes transcribed in the cellular model. In some embodiments, the library may be screened in an animal model (e.g., disease mouse model, wild type non-human primate, etc.) and cells of interest assessed for expression levels from each candidate enhancer/promoter (e.g., enhancer/core promoter) by quantifying levels of barcodes transcribed. [0217] Candidate enhancers may be selected from an enhancer/promoter (e.g., enhancer/core promoter) library based on the results from the high-throughput screening method. In some embodiments, candidate enhancers may be selected by comparison of their activities in different cell types. In some embodiments, candidate enhancers may be selected by comparison of their activities in different tissue types. [0218] In some embodiments, candidate central nervous system (CNS)-enhancers (CNS- enhancers) may have higher activity in CNS tissues or cell types than other tissue or cell types. In some embodiments, candidate CNS-enhancers may have higher activity in LUHMES cells than HepG2 cells. In some embodiments, candidate CNS-enhancers may have higher activity in H4 cells than HepG2 cells. In some embodiments, candidate CNS-enhancers may have higher activity in K562 cells than HepG2 cells. In some embodiments, candidate CNS-enhancers may have higher activity in mouse primary neurons than HepG2 cells. In some embodiments, candidate CNS-enhancers may have higher activity in human induced pluripotent stem cell derived neurons than HepG2 cells. In some embodiments, candidate CNS-enhancers may have higher activity in mouse brain tissues than HepG2 cells. In some embodiments, candidate CNS- enhancers may have higher activity in mouse brain tissues than mouse liver tissues. In some embodiments, candidate CNS-enhancers may have higher activity in mouse brain tissues than mouse liver, heart, kidney, gastrocnemius, or lung tissues. Examples of CNS-enhancers, -98- ^{Docket No. 421688-718021 (718WO1)} identified from an enhancer/promoter (e.g., enhancer/core promoter) library, are provided in TABLE 1. [0219] In some embodiments, candidate liver-enhancer sequences may have higher activity in liver tissues or liver cell types than other non-liver tissues or non-liver cell types. In some embodiments, candidate liver-enhancer sequences may have higher activity in HepG2 cells than LUHMES cells. In some embodiments, candidate liver-enhancer sequences may have higher activity in HepG2 cells than H4 cells. In some embodiments, candidate liver-enhancer sequences may have higher activity in HepG2 cells than K562 cells. In some embodiments, candidate liver- enhancer sequences may have higher activity in mouse liver tissues than mouse brain tissues. In some embodiments, candidate liver-enhancer sequences may have higher activity in mouse liver tissues than mouse brain, heart, kidney, gastrocnemius, or lung tissues. Examples of liver- enhancer sequences, identified from an enhancer/promoter (e.g., enhancer/core promoter) library, include SEQ ID NO: 362 and SEQ ID NO: 386. Payloads [0220] A payload of the present disclosure may comprise a sequence encoding a protein under transcriptional control of a promoter (e.g., a promoter comprising an enhancer and a core promoter). For example, a payload of the present disclosure may comprise a sequence encoding a protein under transcriptional control of a CNS-enhancer and a core promoter. For example, a payload of the present disclosure may comprise a sequence encoding a protein under transcriptional control of a liver-enhancer and a core promoter. The payload may comprise a transgene for delivery to a cell (e.g., a cell of a human or non-human subject). In some embodiments, the transgene may comprise a coding sequence encoding a protein (e.g., a protein without a mutation associated with a disease or condition). Upon delivery of the payload to a cell, the protein encoded by the coding sequence may be expressed in the cell. In some embodiments, expression of a protein encoded by the coding sequence may treat, prevent, or alleviate symptoms of a disease or disorder. In some embodiments, the transgene may encode a wild type copy of a protein that is mutated or dysregulated in the disease or condition. [0221] In some embodiments, genes may be delivered as transgenes to a cell of a subject to treat a disease or condition in the subject. In some embodiments, the genes may be targeted by a protein (e.g., an antibody). [0222] In some embodiments, the payload may comprise a therapeutic polynucleotide. In some embodiments, therapeutic polynucleotide encoded by the coding sequence may treat, prevent, or alleviate symptoms of a disease or disorder. In some embodiments, the payload may comprise a -99- ^{Docket No. 421688-718021 (718WO1)} guide RNA sequence (e.g., for RNA or DNA editing), a tracrRNA, an siRNA, an shRNA, or an miRNA, an antisense oligonucleotide (e.g., for expression knockdown), a structural element (e.g., an RNA hairpin), or combinations thereof. In some embodiments, the payload may encode a guide RNA for adenosine deaminases acting on RNA (ADAR) editing. In some embodiments, the guide RNA may include a targeting sequence having sufficient complementarity to a target RNA to allow for hybridization of the targeting sequence to the target RNA. In some embodiments, the targeting sequence has a minimum antisense complementarity of about 50, 60, 70, 80, 90, 1000r more nucleotides or more to the target RNA. In some embodiments, the guide RNA is 20 to 400 nucleotide residues long. In some embodiments, the guide RNA sequence is 50-200 nucleotide residues long. In some embodiments, the guide RNA sequence is 80-150 nucleotide residues long. [0223] In some embodiments, the payload may be a tRNA targeting a gene associated with a disease or a condition. In some embodiments, the payload may be a tRNA designed to change the amino acid selected for protein synthesis. In some embodiments, the payload may be a tRNA designed to rescue a nonsense mutation which may result in premature stop codon. [0224] In some embodiments, the payload may comprise polypeptides that form one or more functional antibodies or antibody-based compositions. As used herein, the term “antibody” is referred to in the broadest sense and specifically covers various embodiments including, but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), and antibody fragments (e.g., diabodies) so long as they exhibit a desired biological activity (e.g., “functional”). Antibodies are primarily amino-acid based molecules but may also comprise one or more modifications (including, but not limited to the addition of sugar moieties, fluorescent moieties, chemical tags, etc.). Antibodies may be monomeric or multi-merit polypeptides which comprise at least one amino- acid region derived from a known or parental antibody sequence and at least one amino acid region derived from a non-antibody sequence, e.g., mammalian protein. The encoded antibodies may be therapeutic, diagnostic, or for research purposes. Further, payloads described herein of the invention may include fragments of such antibodies or antibodies that have been developed to comprise one or more of such fragments (e.g., variable domains or complementarily determining regions (CDRs)). [0225] In some embodiments, cell or tissue type specific transcription of a transgene sequence is desired. For example, a transgene may be specifically transcribed in cells (e.g., neurons) or tissues (e.g., CNS tissues) of interest. In another example, a transgene lacking a mutation may be specifically transcribed in cells (e.g., liver cells) or tissues (e.g., liver tissue) of interest. -100- ^{Docket No. 421688-718021 (718WO1)} Examples of genes that may be encoded in the payload (e.g., a transgene) or targeted by a protein or polynucleotide encoded in the payload are provided in TABLE 3. In some embodiments, the genes may be delivered as transgenes to a cell of a subject to treat a disease or condition in the subject. In some embodiments, the genes may be targeted by a protein (e.g., an antibody) or a polynucleotide (e.g., a guide RNA) encoded by the payload in a cell of a subject to treat a disease or condition in the subject. [0226] In some embodiments, a payload may be under transcriptional control of a tissue-specific enhancer for tissue-specific expression. For example, a payload may be under transcriptional control of a CNS-enhancer (e.g., any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) for CNS-specific expression of the payload. In another example, a payload may be under transcriptional control of a liver-enhancer (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) for liver-specific expression of the payload. TABLE 3 – Exemplary Payloads or Targets and Indications Payload or Target Condition CNS Payloads and Conditions AADC AADC Deficiency, Parkinson’s Disease ABCD1 Adrenomyeloneuropathy APOE Alzheimer’s Disease APP Alzheimer’s Disease ASPA Canavan Disease ATP7B Wilson’s disease C9orf72 Amyotrophic Lateral Sclerosis (ALS) CLN1 Batten Disease CLN1 CLN1 Disease CLN2 Batten Disease CLN3 Batten Disease CLN4 Batten Disease CLN5 Batten Disease CLN6 Batten Disease CYP46A1 Huntington’s Disease DYRK1A Down syndrome EPM2A or EPM2B Parkinson’s Disease FXN Freidreich’s Ataxia GAD Parkinson’s Disease -101- ^{Docket No. 421688-718021 (718WO1)} Payload or Target Condition CNS Payloads and Conditions GALC Krabbe Disease GBA Gaucher disease type 2 GBA1 Parkinson’s Disease with GBA1 mutations (PD- GBA), Neuronpathic Gaucher’s Disease, Synucleinopathies GDNF Parkinson’s Disease GLA Fabry Disease GLB1 GM1 Gangliosidosis GRN Frontotemporal dementia with GRN mutations (FTD-GRN) HEXA Tay-Sachs Disease HEXB Sandhoff Disease, Gm2 Gangliosidosis hFMR1 Parkinson’s Disease hFOXG1 Parkinson’s Disease hKCNQ2 Parkinson’s Disease hNAGLU Sanfilippo Disease type B hSLC6A1 Epileptic Encephalopathy HTT Huntington’s Disease IT15 Huntington’s Disease, Protocki-Lupski Syndrome LAMP2 Danon Disease LRRK2 Parkinson’s Disease MAPT Alzheimer’s Disease, Tauopathies, Corticobasal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE) MECP2 Rett syndrome NAGLU MPS-IIIB NRTN Parkinson’s Disease NGF Alzheimer’s Disease NTN Parkinson’s Disease OTC Ornithine Transcarbamylase Deficiency RAB7A Charcot-Marie-Tooth neuropathy SGSH Sanfilippo disease type A SMN1 Spinal Muscular Atrophy SNCA Alzheimer’s Disease, Synucleinopathies, Parkinson’s disease -102- ^{Docket No. 421688-718021 (718WO1)} Payload or Target Condition CNS Payloads and Conditions SOD1 Amyotrophic Lateral Sclerosis (ALS) SURF1 Leigh Syndrome TERT Alzheimer’s Disease UBE3A-ATS Angelman Syndrome Liver Payloads and Conditions F8 Haemophilia A OTC Ornithine transcarbamylase deficiency F9 Haemophilia B MCEE Methylmalonic acidemia SERPINA1 Alpha-1-antitrypsin deficiency [0227] Examples of genes that may be encoded by a payload (e.g., the transgene) and delivered to a cell of a subject to treat, prevent, or alleviate symptoms of a disease or condition include AADC, ABCD1, APOE, APP, ASPA, ATP7B, C9orf72, CLN1, CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, CYP46A1, DYRK1A, EPM2A, EPM2B, FXN, GAD, GALC, GBA , GBA1, GDNF, GLA, GLB1, GRN, HEXA, HEXB, hFMR1, hFOXG1, hKCNQ2, hNAGLU, hSLC6A1, HTT, IT15, LAMP2, LRRK2, MAPT, MECP2, NAGLU, NRTN, NGF, NTN, OTC, RAB7A, SGSH, SMN1, SNCA, SOD1, SURF1, TERT, or UBE3A-ATS. In some embodiments, a payload may encode a polynucleotide (e.g., an siRNA, an miRNA, an shRNA, a guide RNA, or a suppressor tRNA) or protein targeting AADC, ABCD1, APOE, APP, ASPA, ATP7B, C9orf72, CLN1, CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, CYP46A1 , DYRK1A, EPM2A, EPM2B, FXN, GAD, GALC, GBA, GBA1, GDNF , GLA, GLB1, GRN, HEXA, HEXB, hFMR1, hFOXG1, hKCNQ2, hNAGLU, hSLC6A1, HTT, IT15, LAMP2, LRRK2, MAPT, MECP2, NAGLU, NRTN, NGF, NTN, OTC, RAB7A, SGSH, SMN1, SNCA, SOD1, SURF1, TERT, or UBE3A-ATS. [0228] In some embodiments, the polynucleotides or proteins that may be encoded by a payload (e.g., the transgene) and delivered to a cell of a subject to treat, prevent, or alleviate symptoms of a disease or condition may be associated with a disease or disorder. In some embodiments, the disease or disorder may be a central nervous system disease or disorder. For example, the payload may encode or target AADC associated with AADC Deficiency or Parkinson’s Disease; ABCD1 associated with Adrenomyeloneuropathy; APOE associated with Alzheimer’s Disease; APP associated with Alzheimer’s Disease; ASPA associated with Canavan Disease; ATP7B associated with Wilson’s disease; C9orf72 associated with Amyotrophic Lateral Sclerosis -103- ^{Docket No. 421688-718021 (718WO1)} (ALS); CLN1 associated with Batten Disease; CLN1 associated with CLN1 Disease; CLN2 associated with Batten Disease; CLN3 associated with Batten Disease; CLN4 associated with Batten Disease; CLN5 associated with Batten Disease; CLN6 associated with Batten Disease; CYP46A1 associated with Huntington’s Disease; DYRK1A associated with Down syndrome; EPM2A or EPM2B associated with Parkinson’s Disease; FXN associated with Freidreich’s Ataxia; GAD associated with Parkinson’s Disease; GALC associated with Krabbe Disease; GBA associated with Gaucher disease type 2; GBA1 associated with Parkinson’s Disease with GBA1 mutations (PD-GBA), Neuronpathic Gaucher’s Disease, or Synucleinopathies; GDNF associated with Parkinson’s Disease; GLA associated with Fabry Disease; GLB1 associated with GM1 Gangliosidosis; GRN associated with Frontotemporal dementia with GRN mutations (FTD- GRN); HEXA associated with Tay-Sachs Disease; HEXB associated with Sandhoff Disease, Gm2 Gangliosidosis.; hFMR1 associated with Parkinson’s Disease; hFOXG1 associated with Parkinson’s Disease; hKCNQ2 associated with Parkinson’s Disease; hNAGLU associated with Sanfilippo Disease type B; hSLC6A1 associated with Epileptic Encephalopathy; HTT associated with Huntington’s Disease; IT15 associated with Huntington’s Disease or Protocki-Lupski Syndrome; LAMP2 associated with Danon Disease; LRRK2 associated with Parkinson’s Disease; MAPT associated with Alzheimer’s Disease, Tauopathies, Corticobasal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), or Chronic Traumatic Encephalopathy (CTE); MECP2 associated with Rett syndrome; NAGLU associated with MPS-IIIB; NRTN associated with Parkinson’s Disease; NGF associated with Alzheimer’s Disease; NTN associated with Parkinson’s Disease; OTC associated with Ornithine Transcarbamylase Deficiency; RAB7A associated with Charcot-Marie-Tooth neuropathy; SGSH associated with Sanfilippo disease type A; SMN1 associated with Spinal Muscular Atrophy; SNCA associated with Alzheimer’s Disease, Synucleinopathies, or Parkinson’s disease; SOD1 associated with Amyotrophic Lateral Sclerosis (ALS); SURF1 associated with Leigh Syndrome; TERT associated with Alzheimer’s Disease; or UBE3A-ATS associated with Angelman Syndrome. [0229] The payload of the recombinant polynucleotide may encode progranulin. Therefore, the protein expressed from the recombinant polynucleotide may be progranulin. In some embodiments, the progranulin is mouse progranulin. In some embodiments, the progranulin is human progranulin. In some embodiments, the payload sequence is a GRN sequence. Exemplary payload sequences are shown in TABLE 4. -104- ^{Docket No. 421688-718021 (718WO1)} TABLE 4 – Exemplary Payload Sequences Payload SEQ ID Sequence NO: Progranulin SEQ ID ATGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTG Coding NO: 350 GAACGCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGA Sequence CCCCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGGACAAATGG CCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCC ACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGT TGCTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCT GCCCACGGGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAG ATCAGGTAACAACTCCGTGGGTGCCATCCAGTGCCCTGATAGTCAGTTC GAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGG GGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTG CTGTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACA CCCACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACT AACAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTCCGGACGCACGGT CCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTA TGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCAC TGCTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCT CCAAGGAGAACGCTACCACGGACCTCCTCACTAAGCTGCCTGCGCACAC AGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAGATGGCTA TACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACC CAGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTA CGTGTGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGC CCTGGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAG CCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCCTC CGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATC CCAGAGGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCT ACACGTGTGTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGG CTGGACTGGAGAAGATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAG AGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTG CTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCT GTGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCA ACGTGAAGGCTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGC CACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAGTGT GGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAAC CGACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTG ATCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTAC CAAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGACGCCCCTTTGAGGGA CCCAGCCTTGAGACAGCTGCTGTGA Codon SEQ ID ATGTGGACCCTTGTAAGTTGGGTAGCGCTCACTGCAGGACTTGTAGCAG optimized NO: 351 GCACTAGATGTCCAGATGGACAATTTTGTCCAGTGGCTTGCTGCCTCGA progranulin TCCCGGTGGAGCTTCATATTCATGTTGTCGCCCGCTTTTGGATAAATGGC coding CTACCACGCTCAGTCGACACCTTGGAGGTCCCTGCCAGGTCGACGCCCA sequence CTGTAGCGCCGGACACTCCTGTATTTTCACTGTGTCTGGTACAAGTAGCT GTTGCCCCTTCCCGGAGGCCGTCGCTTGCGGGGATGGACACCATTGCTG TCCAAGAGGGTTCCATTGCAGTGCCGACGGGAGGAGCTGCTTCCAAAG GTCCGGGAACAACAGTGTCGGAGCCATACAGTGCCCAGATAGTCAGTT CGAATGTCCTGACTTCTCTACCTGTTGCGTGATGGTTGATGGAAGCTGG GGCTGCTGCCCTATGCCCCAAGCCTCATGTTGTGAAGACAGAGTCCACT GCTGCCCTCATGGCGCATTCTGTGATCTCGTACATACTCGCTGCATTACG CCTACTGGAACGCATCCGTTGGCGAAGAAGTTGCCGGCCCAAAGAACG AATAGGGCAGTAGCATTGTCTTCCTCCGTAATGTGCCCCGATGCGCGGT CCCGATGTCCAGATGGCTCAACATGTTGTGAACTGCCTAGTGGAAAGTA TGGTTGTTGTCCAATGCCTAATGCCACCTGTTGTTCCGACCATTTGCATT GCTGCCCTCAGGATACGGTCTGTGACCTGATACAATCTAAATGCCTCTC CAAAGAGAATGCTACGACGGATTTGCTCACTAAACTTCCCGCACATACA GTTGGAGACGTGAAGTGTGACATGGAGGTGTCCTGCCCTGATGGATACA CATGTTGCCGGCTTCAGTCCGGGGCATGGGGATGCTGTCCATTCACTCA AGCCGTATGTTGTGAGGACCACATCCACTGCTGTCCAGCCGGATTTACA -105- ^{Docket No. 421688-718021 (718WO1)} Payload SEQ ID Sequence NO: TGCGACACCCAGAAGGGAACATGTGAACAGGGACCACATCAAGTCCCG TGGATGGAGAAAGCACCTGCCCATCTGTCTTTGCCAGATCCCCAGGCCT TGAAACGGGACGTCCCCTGTGATAACGTTAGCAGTTGTCCTTCCTCAGA CACTTGTTGTCAGTTGACGAGCGGCGAGTGGGGTTGTTGTCCCATTCCG GAGGCGGTGTGTTGCTCAGATCATCAGCACTGCTGCCCCCAGGGTTACA CCTGTGTGGCTGAAGGTCAATGTCAGAGAGGCTCAGAAATAGTTGCTGG GCTGGAGAAGATGCCAGCCAGAAGAGCGTCACTGTCTCACCCCAGAGA TATTGGTTGCGACCAGCACACCAGTTGCCCAGTAGGGCAAACCTGTTGT CCGTCTCTTGGGGGAAGCTGGGCATGTTGCCAACTGCCGCACGCTGTAT GTTGCGAGGACCGCCAGCACTGTTGCCCAGCGGGCTACACTTGCAATGT CAAGGCGCGGAGCTGCGAGAAGGAGGTCGTGAGTGCTCAGCCCGCGAC CTTCTTGGCACGATCCCCCCATGTGGGCGTTAAAGACGTGGAATGCGGC GAGGGTCACTTTTGTCATGATAATCAAACTTGCTGTAGGGATAACAGGC AGGGTTGGGCGTGTTGTCCGTACAGACAGGGCGTATGCTGCGCTGATCG CCGACACTGCTGTCCCGCTGGCTTTCGCTGCGCAGCGCGCGGTACAAAG TGCCTGAGACGCGAGGCTCCTAGATGGGACGCACCACTTAGAGATCCTG CACTGCGGCAGCTTTTGTGA hGRN (no SEQ ID ATGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTG stop codon) NO: 356 GAACGCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGA CCCCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGGACAAATGG CCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCC ACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGT TGCTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCT GCCCACGGGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAG ATCAGGTAACAACTCCGTGGGTGCCATCCAGTGCCCTGATAGTCAGTTC GAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGG GGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTG CTGTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACA CCCACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACT AACAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTCCGGACGCACGGT CCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTA TGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCAC TGCTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCT CCAAGGAGAACGCTACCACGGACCTCCTCACTAAGCTGCCTGCGCACAC AGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAGATGGCTA TACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACC CAGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTA CGTGTGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGC CCTGGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAG CCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCCTC CGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATC CCAGAGGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCT ACACGTGTGTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGG CTGGACTGGAGAAGATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAG AGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTG CTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCT GTGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCA ACGTGAAGGCTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGC CACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAGTGT GGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAAC CGACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTG ATCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTAC CAAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGACGCCCCTTTGAGGGA CCCAGCCTTGAGACAGCTGCTG GRN Coding SEQ ID TGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGG Seq with NO: 357 AACGCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGAC intron9 CCCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGGACAAATGGC CCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCCA CTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTT -106- ^{Docket No. 421688-718021 (718WO1)} Payload SEQ ID Sequence NO: GCTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTG CCCACGGGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGA TCAGGTAACAACTCCGTGGGTGCCATCCAGTGCCCTGATAGTCAGTTCG AATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGGG GTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGC TGTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACAC CCACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACTA ACAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTCCGGACGCACGGTC CCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTAT GGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACT GCTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTC CAAGGAGAACGCTACCACGGACCTCCTCACTAAGCTGCCTGCGCACAC AGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAGATGGCTA TACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACC CAGGTACCCAGGGGTGGCGGGTGGGTGGGCTGAGCACAGTGTGGCAGG CAGCCGGGCCCCAGTGCCCACCTGCCCTTCTTCATCTGCCCTAGGCTGT GTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTGTGAC ACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATG GAGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAGCCTTGAAG AGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCCTCCGATACCT GCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAGGC TGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGT GTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTG GAGAAGATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAGAGACATCG GCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTGCTGCCCGA GCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTG CGAGGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAA GGCTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGCCACCTTC CTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAGTGTGGGGAA GGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACCGACAG GGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGGC GCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTG TTTGCGCAGGGAGGCCCCGCGCTGGGACGCCCCTTTGAGGGACCCAGCC TTGAGACAGCTGCTGTGA GRN signal SEQ ID ATGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTG peptide NO: 358 GA GRN Coding SEQ ID ACGCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACC (minus signal NO: 359 CCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGGACAAATGGCC peptide) CACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCCAC TGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTG CTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGC CCACGGGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGAT CAGGTAACAACTCCGTGGGTGCCATCCAGTGCCCTGATAGTCAGTTCGA ATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGGGG TGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCT GTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACACC CACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACTAA CAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTCCGGACGCACGGTCC CGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTATG GCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTG CTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCC AAGGAGAACGCTACCACGGACCTCCTCACTAAGCTGCCTGCGCACACA GTGGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAGATGGCTAT ACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCC AGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTAC GTGTGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCC CTGGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAGC CTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCCTCC GATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCC -107- ^{Docket No. 421688-718021 (718WO1)} Payload SEQ ID Sequence NO: CAGAGGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTA CACGTGTGTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGGC TGGACTGGAGAAGATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAGA GACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTGC TGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTG TGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAA CGTGAAGGCTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGCC ACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAGTGTG GGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACC GACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGA TCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACC AAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGACGCCCCTTTGAGGGAC CCAGCCTTGAGACAGCTGCTGTGA [0230] In some embodiments, the recombinant polynucleotide comprises a payload sequence (also referred to as a “coding sequence” or a “payload sequence”), wherein the payload is a transgene encoding a progranulin (e.g., GRN sequence). In some embodiments, the recombinant polynucleotide comprises a payload sequence encoding a protein, wherein the protein is human progranulin (e.g., hGRN sequence). The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 80% sequence identity to SEQ ID NO: 350. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 85% sequence identity to SEQ ID NO: 350. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 90% sequence identity to SEQ ID NO: 350. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 95% sequence identity to SEQ ID NO: 350. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 96% sequence identity to SEQ ID NO: 350. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 97% sequence identity to SEQ ID NO: 350. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 98% sequence identity to SEQ ID NO: 350. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 99% sequence identity to SEQ ID NO: 350. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise 100% sequence identity to SEQ ID NO: 350. The recombinant polynucleotide may comprise a payload sequence encoding human progranulin (e.g., hGRN sequence) having a sequence of SEQ ID NO: 350. The recombinant polynucleotide may comprise a payload sequence encoding human progranulin (e.g., hGRN sequence) that is codon optimized (e.g., a codon optimized variation of SEQ ID NO: 350). [0231] The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 80% sequence identity to SEQ ID NO: 351. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 85% sequence identity to SEQ -108- ^{Docket No. 421688-718021 (718WO1)} ID NO: 351. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 90% sequence identity to SEQ ID NO: 351. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 95% sequence identity to SEQ ID NO: 351. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 96% sequence identity to SEQ ID NO: 351. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 97% sequence identity to SEQ ID NO: 351. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 98% sequence identity to SEQ ID NO: 351. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 99% sequence identity to SEQ ID NO: 351. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise 100% sequence identity to SEQ ID NO: 351. The recombinant polynucleotide may comprise a payload sequence encoding human progranulin (e.g., hGRN sequence) having a sequence of SEQ ID NO: 351. The recombinant polynucleotide may comprise a payload sequence encoding human progranulin (e.g., hGRN sequence) that is codon optimized (e.g., SEQ ID NO: 351). [0232] The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 80% sequence identity to SEQ ID NO: 356. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 85% sequence identity to SEQ ID NO: 356. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 90% sequence identity to SEQ ID NO: 356. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 95% sequence identity to SEQ ID NO: 356. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 96% sequence identity to SEQ ID NO: 356. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 97% sequence identity to SEQ ID NO: 356. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 98% sequence identity to SEQ ID NO: 356. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 99% sequence identity to SEQ ID NO: 356. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise 100% sequence identity to SEQ ID NO: 356. The recombinant polynucleotide may comprise a payload sequence encoding human progranulin (e.g., hGRN sequence) having a sequence of SEQ ID NO: 356. The recombinant polynucleotide may comprise a payload sequence encoding human progranulin (e.g., hGRN sequence) that is codon optimized (e.g., a codon optimized variation of SEQ ID NO: 356). -109- ^{Docket No. 421688-718021 (718WO1)} [0233] The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 80% sequence identity to SEQ ID NO: 357. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 85% sequence identity to SEQ ID NO: 357. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 90% sequence identity to SEQ ID NO: 357. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 95% sequence identity to SEQ ID NO: 357. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 96% sequence identity to SEQ ID NO: 357. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 97% sequence identity to SEQ ID NO: 357. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 98% sequence identity to SEQ ID NO: 357. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 99% sequence identity to SEQ ID NO: 357. The payload sequence encoding human progranulin (e.g., hGRN sequence) may comprise 100% sequence identity to SEQ ID NO: 357. The recombinant polynucleotide may comprise a payload sequence encoding human progranulin (e.g., hGRN sequence) having a sequence of SEQ ID NO: 357. The recombinant polynucleotide may comprise a payload sequence encoding human progranulin (e.g., hGRN sequence) that is codon optimized (e.g., a codon optimized variation of SEQ ID NO: 357). [0234] In some embodiments, the sequence encoding human progranulin (e.g., hGRN sequence) may comprise a sequence encoding a signal peptide. For example, SEQ ID NO: 350, SEQ ID NO: 351, SEQ ID NO: 356, and SEQ ID NO: 357 encoding human progranulin comprise a sequence encoding a signal peptide. The signal peptide may be part of the progranulin protein (e.g., SEQ ID NO: 352) encoded by the coding sequence. The signal peptide may be encoded by a sequence having at least 80% sequence identity to SEQ ID NO: 358. The signal peptide may be encoded by a sequence having at least 85% sequence identity to SEQ ID NO: 358. The signal peptide may be encoded by a sequence having at least 90% sequence identity to SEQ ID NO: 358. The signal peptide may be encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 358. The signal peptide may be encoded by a sequence having at least 96% sequence identity to SEQ ID NO: 358. The signal peptide may be encoded by a sequence having at least 97% sequence identity to SEQ ID NO: 358. The signal peptide may be encoded by a sequence having at least 98% sequence identity to SEQ ID NO: 358. The signal peptide may be encoded by a sequence having at least 99% sequence identity to SEQ ID NO: 358. The signal peptide may be encoded by a sequence having 100% sequence identity to SEQ ID NO: 358. The signal peptide may be encoded by a sequence of SEQ ID NO: 358. The sequence encoding the -110- ^{Docket No. 421688-718021 (718WO1)} signal peptide may be positioned upstream of a progranulin coding sequence (e.g., SEQ ID NO: 359). [0235] The sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 80% sequence identity to SEQ ID NO: 359. The sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 85% sequence identity to SEQ ID NO: 359. The sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 90% sequence identity to SEQ ID NO: 359. The sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 95% sequence identity to SEQ ID NO: 359. The sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 96% sequence identity to SEQ ID NO: 359. The sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 97% sequence identity to SEQ ID NO: 359. The sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 98% sequence identity to SEQ ID NO: 359. The sequence encoding human progranulin (e.g., hGRN sequence) may comprise at least 99% sequence identity to SEQ ID NO: 359. The sequence encoding human progranulin (e.g., hGRN sequence) may comprise 100% sequence identity to SEQ ID NO: 359. The recombinant polynucleotide may comprise a sequence encoding human progranulin (e.g., hGRN sequence) having a sequence of SEQ ID NO: 359. [0236] In some embodiments, a coding sequence (e.g., a payload sequence encoding human progranulin) of a recombinant polynucleotide of the present disclosure encodes progranulin protein (e.g., a human progranulin). The coding sequence may encode a protein comprising at least 80% sequence identity to SEQ ID NO: 352 (MWTLVSWVALTAGLVAGTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLG GPCQVDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSG NNSVGAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVH TRCITPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMP NATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGY TCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHL SLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCV AEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLP HAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCH DNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLR DPALRQLL). The coding sequence may encode a protein comprising at least 85% sequence identity to SEQ ID NO: 352. The coding sequence may encode a protein comprising at least 90% sequence identity to SEQ ID NO: 352. The coding sequence may encode a protein -111- ^{Docket No. 421688-718021 (718WO1)} comprising at least 95% sequence identity to SEQ ID NO: 352. The coding sequence may encode a protein comprising at least 96% sequence identity to SEQ ID NO: 352. The coding sequence may encode a protein comprising at least 97% sequence identity to SEQ ID NO: 352. The coding sequence may encode a protein comprising at least 98% sequence identity to SEQ ID NO: 352. The coding sequence may encode a protein comprising at least 99% sequence identity to SEQ ID NO: 352. The coding sequence may encode a protein comprising 100% sequence identity to SEQ ID NO: 352. The coding sequence may encode a protein comprising a sequence of SEQ ID NO: 352. [0237] Examples of genes that may be encoded by a payload sequence (e.g., the transgene) and delivered to a cell of a subject to treat, prevent, or alleviate symptoms of a disease or condition include F8, OTC, F9, MCEE, or SERPINA1. In some embodiments, a payload may encode a polynucleotide (e.g., an siRNA, an miRNA, an shRNA, a guide RNA, or a suppressor tRNA) or protein targeting F8, OTC, F9, MCEE, or SERPINA1. [0238] In some embodiments, the polynucleotides or proteins that may be encoded by a payload sequence (e.g., the transgene) and delivered to a cell of a subject to treat, prevent, or alleviate symptoms of a disease or condition may be associated with a disease or disorder. In some embodiments, the disease or disorder may be a liver disease or disorder. For example, the payload may encode or target F8 associated with Haemophilia A; OTC associated with Ornithine transcarbamylase deficiency; F9 associated with Haemophilia B; MCEE associated with Methylmalonic acidemia; or SERPINA1 associated with Alpha-1-antitrypsin deficiency. [0239] In some embodiments, a gene encoded by a payload (e.g., the transgene) may be transcribed in target cell type or tissue type at a level that is at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5- fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold higher a transcription level of the payload in a non-target cell type or tissue type. [0240] In some embodiments, the a payload may be under transcriptional control of a CNS- enhancer (e.g., any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) that may activate transcription in a CNS cell or CNS tissue at a level that is at least about -0.75-fold, at least about -0.5-fold, at least about -0.25-fold, at least about -0.1-fold, at least about 0-fold, at least about 0.1-fold, at least about 0.25-fold, at least about 0.5-fold, at least about 0.75-fold, at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least -112- ^{Docket No. 421688-718021 (718WO1)} about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10- fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold a transcription level of a non-CNS cell type or non-CNS tissue type. [0241] In some embodiments, the a payload may be under transcriptional control of a liver- enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) that may activate transcription in a liver cell or liver tissue at a level that is at least about -0.75-fold, at least about -0.5-fold, at least about -0.25-fold, at least about -0.1-fold, at least about 0-fold, at least about 0.1-fold, at least about 0.25-fold, at least about 0.5-fold, at least about 0.75-fold, at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5- fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold a transcription level of a non-liver cell type or non-liver tissue type. [0242] In some embodiments, a gene encoded by a payload (e.g., the transgene) may be transcribed in target cell type or tissue type at a level that is at least about -0.75-fold, at least about -0.5-fold, at least about -0.25-fold, at least about -0.1-fold, at least about 0-fold, at least about 0.1-fold, at least about 0.25-fold, at least about 0.5-fold, at least about 0.75-fold, at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold a transcription level of a wildtype version of the payload in a target cell type or tissue type. [0243] In some embodiments, the a payload may be under transcriptional control of a CNS- enhancer (e.g., any of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385) that may activate transcription in a CNS cell or CNS tissue a level that is at least about -0.75-fold, at least about -0.5-fold, at least about -0.25-fold, at least about -0.1-fold, at least about 0-fold, at least about 0.1-fold, at least about 0.25-fold, at least about 0.5-fold, at least about 0.75-fold, at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10- fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at -113- ^{Docket No. 421688-718021 (718WO1)} least about 100-fold, at least about 150-fold, or at least about 200-fold a transcription level of a wildtype version of the payload in a CNS cell or CNS tissue. [0244] In some embodiments, the a payload may be under transcriptional control of a liver- enhancer sequence (e.g., SEQ ID NO: 362 or SEQ ID NO: 386) that may activate transcription in a liver cell or liver tissue a level that is at least about -0.75-fold, at least about -0.5-fold, at least about -0.25-fold, at least about -0.1-fold, at least about 0-fold, at least about 0.1-fold, at least about 0.25-fold, at least about 0.5-fold, at least about 0.75-fold, at least about 1-fold, at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5- fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, or at least about 200-fold a transcription level of a wildtype version of the payload in a liver cell or liver tissue. Additional Elements [0245] In some embodiments, the recombinant polynucleotide further comprises additional elements. An additional element may enhance or increase expression of the payload, e.g., enhance or increase expression of a protein encoded by the payload. Examples of additional elements that may be included in a recombinant polynucleotide are a post-transcriptional regulatory element, a polyadenylation signal, a transcriptional pause site, a neuron-restrictive silencer element, a CCCTC-binding factor sequence, a 5’ untranslated region, a 3’ untranslated region, a 5’ stuffer sequence, and combinations thereof. For example, a recombinant polynucleotide comprises additional elements of a post-transcriptional regulatory element, a polyadenylation signal, and a transcriptional pause site. In another example, a post- transcriptional regulatory element, a polyadenylation signal, a transcriptional pause site, a 5’ untranslated region, a 3’ untranslated region, and a 5’ stuffer sequence. [0246] In some embodiments, the recombinant polynucleotide comprises an element that increases expression of the payload, such as a post-transcriptional regulatory element. In some embodiments, the post-transcriptional regulatory element is a woodchuck hepatitis virus post- transcriptional regulatory element (WPRE) or a variant thereof (e.g., a shortened WPRE, WPRE3). In some embodiments, the recombinant polynucleotide is engineered to comprise a polyadenylation (polyA) signal for increased expression of the payload (e.g., progranulin). For example, the recombinant polynucleotide is engineered to comprise a rabbit beta globulin polyA sequence. In some embodiments the recombinant polynucleotide is engineered to comprise an element that reduces transcriptional silencing, such as a transcriptional pause site. In some embodiments, a transcriptional pause site may comprise a polyA signal (e.g., a second polyA -114- ^{Docket No. 421688-718021 (718WO1)} signal). The transcriptional pause site may reduce transcriptional silencing caused by transcriptional readthrough from an upstream promoter. [0247] In some embodiments, an additional element is a post-transcriptional regulatory element, such as a woodchuck post-transcriptional regulatory element (WPRE). In some embodiments, the WPRE is a shortened WPRE, e.g., WPRE3. [0248] In some embodiments, an additional element is a neuron-restrictive silencer element (NRSE). A NRSE may be located either upstream or downstream of the promoter, the enhancer, or both. In some embodiments, the NRSE enhances expression of the payload in neuronal cells. In some embodiments, the NRSE silences expression of the payload in non-neuronal cells. The NRSE may be positioned in the recombinant polynucleotide such that the NRSE regulates cell specificity of payload expression. For example, the NRSE may regulate cell specificity of GRN expression from a recombinant polynucleotide comprising an NRSE and a GRN coding sequence. The NRSE may enhance expression of a payload in neuronal cells, silence expression of the payload in non-neuronal cells, or a combination thereof. In some instances, the NRSE enhances expression of the payload in neuronal cells relative to other cell types by silencing expression of the payload in non-neuronal cells. [0249] In some embodiments, an additional element is a polyadenylation (polyA) signal. The polyA signal sequence may regulate expression of the payload. [0250] In some embodiments, an additional element is a CCCTC-binding factor (CTCF) sequence. A CTCF sequence may modify accessibility of the recombinant polynucleotide to transcription machinery to enhance expression of the payload. The CTCF sequence may be positioned in the recombinant polynucleotide for payload expression such that the CTCF modifies accessibility of the recombinant polynucleotide to transcription machinery to enhance expression of the payload. [0251] In some embodiments, an additional element is a 5’ untranslated region (5’ UTR). The 5’ UTR may be positioned in the recombinant polynucleotide such that the 5’ UTR regulates payload expression. [0252] In some embodiments, an additional element is a 3’ untranslated region (3’ UTR). The 3’ UTR may be positioned in the recombinant polynucleotide such that the 3’ UTR regulates payload expression. The polyA signal sequence may regulate expression of the payload. [0253] In some embodiments, a recombinant polynucleotide comprises a combination of additional elements. For example, a recombinant nucleotide may comprise one or more additional elements selected from the group consisting of a WPRE, an NRSE, a CTCF, a polyA -115- ^{Docket No. 421688-718021 (718WO1)} signal, a 5’ UTR, a 3’ UTR, and combinations thereof. Exemplary sequences of additional elements are shown below in TABLE 5. TABLE 5 – Exemplary Sequences of Additional Elements Element SEQ ID NO: Sequence WPRE SEQ ID NO: CGATAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGG 287 TATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCT TTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTT CTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTG TGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCT GACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTC CTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAAC TCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGT TGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCT TTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGA CGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCC TTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGC CTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCG CATCGG WPRE3 SEQ ID NO: ATCGAATTCCGCTCGAGATAATCAACCTCTGGATTACAAAATTTG 288 TGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTA TGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCC GTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTAGTTCTT GCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACA GGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTTATTTGT GAAATTTGTGATGCTATTGCTTTATTTGTAACCATCTA NRSE + SEQ ID NO: GGCGCTGTCCGTGGTGCTGAACTCGAATTGCGTGGCGCTGTCCGT CTCF 289 GGTGCTGAAGGGCGGCTCGCTGCTGCCCCCTAGCGGGGGAGGGA CGTAATTACATCCCTGG NRSE SEQ ID NO: TTCAGCACCACGGACAGCGCCACGCAATTCGATTCAGCACCACG 290 GACAGCGCC NRSE + SEQ ID NO: CCAGGGATGTAATTACGTCCCTCCCCCGCTAGGGGGCAGCAGCG CTCF 291 AGCCGCCCGGAATCTGCGGGATCTAGACCCGAACCCCGGACGGC GCCCAAGTTTCGTGCCCTTTCTC NRSE SEQ ID NO: GGAATCTGCGGGATCTAGACCCGAACCCCGGACGGCGCCCAAGT 292 TTCGTGCCCTTT NRSE + SEQ ID NO: CCAGGGATGTAATTACGTCCCTCCCCCGCTAGGGGGCAGCAGCG CTCF 293 AGCCGCCCGTTCAGCACCACGGACAGCGCC NRSE SEQ ID NO: GTTCAGCACCACGGACAGCGCC 294 NRSE + SEQ ID NO: GGAGCTGTCCGAGACTCGCGGGGTGCTGAACCTGATGCAGGAGC CTCF 295 TGTCCTCGCCGTGCGTGGTGCTGAAGGGCGGCTCGCTGCTGCCCC CTAGCGGGGGAGGGACGTAATTACATCCCTGG NRSE SEQ ID NO: TTCAGCACCACGCACGGCGAGGACAGCTCCTGCATCAGGTTCAGC 296 ACCCCGCGAGTCTCGGACAGCTCC hHBA13’ SEQ ID NO: GCTGGAGCCTCGGTGGCCATGCTTCTTGCCCCTTGGGCCTCCCCC UTR polyA 297 CAGCCCCTCCTCCCCTTCCTGCACCCGTACCCCCGTGGTCTTTGAA TAAAGTCTGAGTGGGCGGCA hHBB 3’ UTR SEQ ID NO: GCTCGCTTTCTTGCTGTCCAATTTCTATTAAAGGTTCCTTTGTTCC polyA 298 CTAAGTCCAACTACTAAACTGGGGGATATTATGAAGGGCCTTGAG CATCTGGATTCTGCCTAATAAAAAACATTTATTTTCATTGCAA -116- ^{Docket No. 421688-718021 (718WO1)} Element SEQ ID NO: Sequence Rabbit Beta SEQ ID NO: AATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTT globin polyA 299 GTGTCTCTCA Rabbit Beta SEQ ID NO: GATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCC globin polyA 300 CTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTG CAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCG SV40 polyA SEQ ID NO: TTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATC 301 ACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTG GTTTGTCCAAACTCATCAATGTATCTTATCATGTCTG SV40 polyA SEQ ID NO: AGACATGATAAGATACATTGATGAGTTTGGACAAACCACAACAA 302 GAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTA TTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACA ACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGATGT GGGAGGTTTTTTAAAGCAAGTAAAACCTCTACAAATGTGGTA SV40 polyA SEQ ID NO: GCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCAT 303 TATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTT TATGTTTCAGGTTCAGGGGGAGATGTGGGAGGTTTTTTAAAGCGG CCGC polyA SEQ ID NO: AGAGATCCTGCACTGCGGCAGCTTTTGTGAGGTACCAATAAAATA 304 TCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGTGCCATGGC CAATGGCGCGCCGAGCTTGGCTCGAGCA polyA SEQ ID NO: AATAAAAGATCTTTATTTTCATTAGATCTGTGTGTTGGTTTTTTGT 305 GTG polyA SEQ ID NO: AATAAAAGATCCAGAGCTCTAGAGATCTGTGTGTTGGTTTTTTGT 306 GTG 5'ITR SEQ ID NO: TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGCC 307 CGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTC AGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCA CTAGGGGTTCCT 3'ITR SEQ ID NO: AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTC 308 GCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCG ACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGA GGGAGTGGCCAA 5' stuffer SEQ ID NO: GGATCCCTCGAGACGCGTCAATTGCCTAGG 309 5'UTR SEQ ID NO: ATTCCGGGCTAGCGCCGCCACC 310 5’ UTR SEQ ID NO: GCTAGCGCCGCCACC 353 Kozak SEQ ID NO: GCCGCCACC 354 PolyA and SEQ ID NO: AATAAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGT transcriptional 311 GTGAATCGATAGTACTAACATACGCTCTCCATCAAAACAAAACG pause site AAACAAAACAAACTAGCAAAATAGGCTGTCCCCAGTGCAAGTGC AGGTGCCAGAACATTTCTCT [0254] In some embodiments, the recombinant polynucleotide further comprises a post- transcriptional regulatory element, such as a woodchuck hepatitis virus post-transcriptional regulatory element (“WPRE”, also referred to as a “WPRE element”). In some embodiments, a -117- ^{Docket No. 421688-718021 (718WO1)} post-transcriptional regulatory element is included in a 3’untranslated region of a recombinant polynucleotide. A post-transcriptional regulatory element may enhance expression of a payload (e.g., a coding sequence encoding a protein or a polynucleotide) of a recombinant polynucleotide. [0255] The WPRE may comprise at least 80% sequence identity to SEQ ID NO: 287. The WPRE may comprise at least 85% sequence identity to SEQ ID NO: 287. The WPRE may comprise at least 90% sequence identity to SEQ ID NO: 287. The WPRE may comprise at least 95% sequence identity to SEQ ID NO: 287. The WPRE may comprise at least 96% sequence identity to SEQ ID NO: 287. The WPRE may comprise at least 97% sequence identity to SEQ ID NO: 287. The WPRE may comprise at least 98% sequence identity to SEQ ID NO: 287. The WPRE may comprise at least 99% sequence identity to SEQ ID NO: 287. The WPRE may comprise 100% sequence identity to SEQ ID NO: 287. The recombinant polynucleotide may further comprise a WPRE having a sequence of SEQ ID NO: 287. In some embodiments, the WPRE is downstream of the promoter in the recombinant polynucleotide. In some embodiments the WPRE is downstream of the payload sequence. In some embodiments, the recombinant polynucleotide further comprises at least 1, 2, 3, 4, or 5 WPREs. [0256] In some embodiments, the post-transcriptional regulatory element is part of a 3’ untranslated region (3’ UTR). In some embodiments, a 3’ UTR comprises a post-transcriptional regulatory element. [0257] In some embodiments, the WPRE element is a WPRE variant. In some embodiments, the WPRE variant is a shortened WPRE or truncated WPRE. A shorted WPRE or truncated WPRE (e.g., a WPRE3) may exhibit similar transcriptional activity as a full length WPRE. A shorted WPRE or truncated WPRE may be preferred over a full length WPRE due to its shorter nucleotide sequence. In some embodiments, the shortened WPRE is a WPRE3. In some embodiments, the recombinant polynucleotide further comprises a WPRE3. The WPRE3 may comprise at least 80% sequence identity to SEQ ID NO: 288. The WPRE3 may comprise at least 85% sequence identity to SEQ ID NO: 288. The WPRE3 may comprise at least 90% sequence identity to SEQ ID NO: 288. The WPRE3 may comprise at least 95% sequence identity to SEQ ID NO: 288. The WPRE3 may comprise at least 96% sequence identity to SEQ ID NO: 288. The WPRE3 may comprise at least 97% sequence identity to SEQ ID NO: 288. The WPRE3 may comprise at least 98% sequence identity to SEQ ID NO: 288. The WPRE3 may comprise at least 99% sequence identity to SEQ ID NO: 288. The WPRE3 may comprise 100% sequence identity to SEQ ID NO: 288. The recombinant polynucleotide may further comprise a WPRE3 having a sequence of SEQ ID NO: 288. In some embodiments, the WPRE3 is downstream of the -118- ^{Docket No. 421688-718021 (718WO1)} promoter in the recombinant polynucleotide. In some embodiments the WPRE3 is downstream of the payload sequence. In some embodiments, the recombinant polynucleotide further comprises at least 1, 2, 3, 4, or 5 WPRE3s. [0258] In some embodiments, the recombinant polynucleotide further comprises a neuron restrictive silencer element (NRSE). A NRSE may inhibit expression of the payload sequence in non-neuronal cells. The NRSE may comprise at least 80% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. The NRSE may comprise at least 85% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. The NRSE may comprise at least 90% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. The NRSE may comprise at least 95% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. The NRSE may comprise at least 96% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. The NRSE may comprise at least 97% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. The NRSE may comprise at least 98% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. The NRSE may comprise at least 99% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. The NRSE may comprise 100% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296. The recombinant polynucleotide may further comprise a NRSE having a sequence of any one of SEQ ID NO: 289 – SEQ ID NO: 296. In some embodiments, the NRSE is downstream of the promoter in the recombinant polynucleotide. In some embodiments the NRSE is downstream of the payload sequence. In some embodiments, the recombinant polynucleotide further comprises at least 1, 2, 3, 4, or 5 NRSEs. [0259] In some embodiments, the recombinant polynucleotide further comprises an NRSE and a CCCTC-binding factor (CTCF). The NRSE and CTCF may comprise at least 80% sequence identity to SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. The NRSE and CTCF may comprise at least 85% sequence identity to SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. The NRSE and CTCF may comprise at least 90% sequence identity to SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. The NRSE and CTCF may comprise at least 95% sequence identity to SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. The NRSE and CTCF may comprise at least 96% sequence identity to SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. The NRSE and CTCF may comprise at least 97% sequence identity to SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. The NRSE and CTCF may comprise at least 98% sequence identity to SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. The NRSE and CTCF may comprise at least 99% sequence -119- ^{Docket No. 421688-718021 (718WO1)} identity to SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. The NRSE and CTCF may comprise 100% sequence identity to SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. The recombinant polynucleotide may further comprise a NRSE and CTCF having a sequence of SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295. In some embodiments, the NRSE and CTCF is downstream of the promoter in the recombinant polynucleotide. In some embodiments the NRSE and CTCF is downstream of the payload sequence. In some embodiments, the recombinant polynucleotide further comprises at least 1, 2, 3, 4, or 5 NRSEs and CTCFs. [0260] In some embodiments, the recombinant polynucleotide further comprises a polyadenylation (polyA) signal. The polyA signal may signal formation of a polyA tail to an RNA transcribed from the recombinant polynucleotide. The polyA signal may comprise at least 80% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. The polyA signal may comprise at least 85% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. The polyA signal may comprise at least 90% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. The polyA signal may comprise at least 95% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. The polyA signal may comprise at least 96% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. The polyA signal may comprise at least 97% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. The polyA signal may comprise at least 98% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. The polyA signal may comprise at least 99% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. The polyA signal may comprise 100% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306. The recombinant polynucleotide may further comprise a polyA signal having a sequence of any one of SEQ ID NO: 297 – SEQ ID NO: 306. In some embodiments, the polyA signal is downstream of the promoter in the recombinant polynucleotide. In some embodiments the polyA signal is downstream of the payload sequence. In some embodiments, the recombinant polynucleotide further comprises at least 1, 2, 3, 4, or 5 polyA signals. [0261] In preferred embodiments, the polyA signal is a rabbit beta globin polyA signal. The rabbit beta globin rabbit beta globin polyA signal may comprise at least 80% sequence identity to SEQ ID NO: 299. The rabbit beta globin polyA signal may comprise at least 85% sequence identity to SEQ ID NO: 299. The rabbit beta globin polyA signal may comprise at least 90% sequence identity to SEQ ID NO: 299. The rabbit beta globin polyA signal may comprise at least 95% sequence identity to SEQ ID NO: 299. The rabbit beta globin polyA signal may comprise at least 96% sequence identity to SEQ ID NO: 299. The rabbit beta globin polyA signal may -120- ^{Docket No. 421688-718021 (718WO1)} comprise at least 97% sequence identity to SEQ ID NO: 299. The rabbit beta globin polyA signal may comprise at least 98% sequence identity to SEQ ID NO: 299. The rabbit beta globin polyA signal may comprise at least 99% sequence identity to SEQ ID NO: 299. The rabbit beta globin polyA signal may comprise 100% sequence identity to SEQ ID NO: 299. The recombinant polynucleotide may further comprise a rabbit beta globin polyA signal having a sequence of SEQ ID NO: 299. In some embodiments, the rabbit beta globin polyA signal is downstream of the promoter in the recombinant polynucleotide. In some embodiments the rabbit beta globin polyA signal is downstream of the payload sequence. In some embodiments, the recombinant polynucleotide further comprises at least 1, 2, 3, 4, or 5 rabbit beta globin polyA signals. [0262] The polyA signal may comprise at least 80% sequence identity to SEQ ID NO: 297 or SEQ ID NO: 298. The polyA signal may comprise at least 85% sequence identity to SEQ ID NO: 297 or SEQ ID NO: 298. The polyA signal may comprise at least 90% sequence identity to SEQ ID NO: 297 or SEQ ID NO: 298. The polyA signal may comprise at least 95% sequence identity to SEQ ID NO: 297 or SEQ ID NO: 298. The polyA signal may comprise at least 96% sequence identity to SEQ ID NO: 297 or SEQ ID NO: 298. The polyA signal may comprise at least 97% sequence identity to SEQ ID NO: 297 or SEQ ID NO: 298. The polyA signal may comprise at least 98% sequence identity to SEQ ID NO: 297 or SEQ ID NO: 298. The polyA signal may comprise at least 99% sequence identity to SEQ ID NO: 297 or SEQ ID NO: 298. The polyA signal may comprise 100% sequence identity to SEQ ID NO: 297 or SEQ ID NO: 298. The recombinant polynucleotide may further comprise a polyA signal having a sequence of SEQ ID NO: 297 or SEQ ID NO: 298. In some embodiments, the polyA signal is downstream of the promoter in the recombinant polynucleotide. In some embodiments the polyA signal is downstream of the payload sequence. In some embodiments, the recombinant polynucleotide further comprises at least 1, 2, 3, 4, or polyA signals. [0263] In some embodiments, the polyA signal is part of a 3’ untranslated region (3’ UTR). In some embodiments, a 3’ UTR comprises a polyA signal. [0264] In some embodiments, the recombinant polynucleotide further comprises a transcriptional pause site. The transcriptional pause site may facilitate transcriptional termination and prevent transcriptional interference. The transcriptional pause site may reduce transcriptional silencing for example, transcriptional silencing caused by transcriptional readthrough from an upstream promoter. In some embodiments, the transcriptional pause site includes a second polyA signal. The transcriptional pause site may comprise at least 80% sequence identity to SEQ ID NO: 311. The transcriptional pause site may comprise at least 85% -121- ^{Docket No. 421688-718021 (718WO1)} sequence identity to SEQ ID NO: 311. The transcriptional pause site may comprise at least 90% sequence identity to SEQ ID NO: 311. The transcriptional pause site may comprise at least 95% sequence identity to SEQ ID NO: 311. The transcriptional pause site may comprise at least 96% sequence identity to SEQ ID NO: 311. The transcriptional pause site may comprise at least 97% sequence identity to SEQ ID NO: 311. The transcriptional pause site may comprise at least 98% sequence identity to SEQ ID NO: 311. The transcriptional pause site may comprise at least 99% sequence identity to SEQ ID NO: 311. The transcriptional pause site may comprise 100% sequence identity to SEQ ID NO: 311. The recombinant polynucleotide may further comprise a transcriptional pause site having a sequence of SEQ ID NO: 311. In some embodiments, the transcriptional pause site is downstream of the promoter in the recombinant polynucleotide. In some embodiments the transcriptional pause site is downstream of the payload sequence. [0265] In some embodiments, the recombinant polynucleotide further comprises a 5’ untranslated region (5’UTR), such as a minimal 5’ UTR. In some embodiments, the recombinant polynucleotide comprises a 5’ UTR containing an intron. In some embodiments, the recombinant polynucleotide comprises a 5’ UTR; an intron in the 5’ UTR, the payload sequence, or both; and a polyadenylation signal. [0266] In some embodiments, the 5’UTR overlaps with the core promoter. In some embodiments, the overlap is 7 nucleotides, wherein the 7 nucleotides are the 3’ 7 nucleotides of the core promoter. The core promoter can be a minP variant core promoter. The core promoter can comprise SEQ ID NO: 95. The 5’UTR can comprise, from 5’ to 3’, the 3’ 7 nucleotides of SEQ ID NO: 95 and SEQ ID NO: 353. The 5’ UTR can comprise a Kozak sequence downstream of the promoter. The Kozak sequence can comprise SEQ ID NO: 354. The 5’ UTR can comprise, from 5’ to 3’, the 3’ 7 nucleotides of SEQ ID NO: 95 and SEQ ID NO: 354. The 5’ UTR can comprise additional nucleotides between the 3’ 7 nucleotides of the SEQ ID NO: 95 and SEQ ID NO: 354. [0267] The 5’ UTR may comprise at least 80% sequence identity to SEQ ID NO: 310. The 5’ UTR may comprise at least 85% sequence identity to SEQ ID NO: 310. The 5’ UTR may comprise at least 90% sequence identity to SEQ ID NO: 310. The 5’ UTR may comprise at least 95% sequence identity to SEQ ID NO: 310. The 5’ UTR may comprise at least 96% sequence identity to SEQ ID NO: 310. The 5’ UTR may comprise at least 97% sequence identity to SEQ ID NO: 310. The 5’ UTR may comprise at least 98% sequence identity to SEQ ID NO: 310. The 5’ UTR may comprise at least 99% sequence identity to SEQ ID NO: 310. The 5’ UTR may comprise 100% sequence identity to SEQ ID NO: 310. In some embodiments, the 5’ UTR is downstream of the promoter in the recombinant polynucleotide. In some embodiments, the 5’ -122- ^{Docket No. 421688-718021 (718WO1)} UTR overlaps the 3’ end of the promoter. In some embodiments the 5’ UTR is upstream of the payload sequence. [0268] The 5’ UTR may comprise at least 80% sequence identity to SEQ ID NO: 353. The 5’ UTR may comprise at least 85% sequence identity to SEQ ID NO: 353. The 5’ UTR may comprise at least 90% sequence identity to SEQ ID NO: 353. The 5’ UTR may comprise at least 95% sequence identity to SEQ ID NO: 353. The 5’ UTR may comprise at least 96% sequence identity to SEQ ID NO: 353. The 5’ UTR may comprise at least 97% sequence identity to SEQ ID NO: 353. The 5’ UTR may comprise at least 98% sequence identity to SEQ ID NO: 353. The 5’ UTR may comprise at least 99% sequence identity to SEQ ID NO: 353. The 5’ UTR may comprise 100% sequence identity to SEQ ID NO: 353. In some embodiments, the 5’ UTR is downstream of the promoter in the recombinant polynucleotide. In some embodiments, the 5’ UTR overlaps the 3’ end of the promoter. In some embodiments the 5’ UTR is upstream of the payload sequence. [0269] The 5’ UTR may comprise a Kozak sequence. The Kozak sequence may comprise at least 80% sequence identity to SEQ ID NO: 354. The Kozak sequence may comprise at least 85% sequence identity to SEQ ID NO: 354. The Kozak sequence may comprise at least 90% sequence identity to SEQ ID NO: 354. The Kozak sequence may comprise at least 95% sequence identity to SEQ ID NO: 354. The Kozak sequence may comprise at least 96% sequence identity to SEQ ID NO: 354. The Kozak sequence may comprise at least 97% sequence identity to SEQ ID NO: 354. The Kozak sequence may comprise at least 98% sequence identity to SEQ ID NO: 354. The Kozak sequence may comprise at least 99% sequence identity to SEQ ID NO: 354. The Kozak sequence may comprise 100% sequence identity to SEQ ID NO: 354. In some embodiments, the Kozak sequence is downstream of the promoter in the recombinant polynucleotide. In some embodiments the Kozak sequence is upstream of the payload sequence [0270] In some embodiments, the recombinant polynucleotide further comprises a stuffer sequence. The stuffer sequence may comprise at least 80% sequence identity to SEQ ID NO: 309. The stuffer sequence may comprise at least 85% sequence identity to SEQ ID NO: 309. The stuffer sequence may comprise at least 90% sequence identity to SEQ ID NO: 309. The stuffer sequence may comprise at least 95% sequence identity to SEQ ID NO: 309. The stuffer sequence may comprise at least 96% sequence identity to SEQ ID NO: 309. The stuffer sequence may comprise at least 97% sequence identity to SEQ ID NO: 309. The stuffer sequence may comprise at least 98% sequence identity to SEQ ID NO: 309. The stuffer sequence may comprise at least 99% sequence identity to SEQ ID NO: 309. The stuffer -123- ^{Docket No. 421688-718021 (718WO1)} sequence may comprise 100% sequence identity to SEQ ID NO: 309. The recombinant polynucleotide may further comprise a stuffer sequence having a sequence of SEQ ID NO: 309. In some embodiments, the stuffer sequence is upstream of the promoter in the recombinant polynucleotide. In some embodiments the stuffer sequence is upstream of the payload sequence. In some embodiments, the recombinant polynucleotide further comprises at least 1, 2, 3, 4, or stuffer sequences. [0271] In some embodiments, the recombinant polynucleotide further comprises a 5’ inverted terminal repeat (5’ ITR). The 5’ ITR may be selected based on a vector, such as a viral vector, used to deliver the recombinant polynucleotide. In some embodiments, the 5’ ITR may be an AAV 5’ ITR (e.g., an AAV55’ ITR, an AAV15’ ITR, an AAV25’ ITR, an AAV95’ ITR, or a PhP.eB 5’ ITR). The 5’ ITR may comprise at least 80% sequence identity to SEQ ID NO: 307. The 5’ ITR may comprise at least 85% sequence identity to SEQ ID NO: 307. The 5’ ITR may comprise at least 90% sequence identity to SEQ ID NO: 307. The 5’ ITR may comprise at least 95% sequence identity to SEQ ID NO: 307. The 5’ ITR may comprise at least 96% sequence identity to SEQ ID NO: 307. The 5’ ITR may comprise at least 97% sequence identity to SEQ ID NO: 307. The 5’ ITR may comprise at least 98% sequence identity to SEQ ID NO: 307. The 5’ ITR may comprise at least 99% sequence identity to SEQ ID NO: 307. The 5’ ITR may comprise 100% sequence identity to SEQ ID NO: 307. In some embodiments, the 5’ ITR is upstream of the promoter in the recombinant polynucleotide. In some embodiments the 5’ ITR is upstream of the payload sequence. In some embodiments, the recombinant polynucleotide comprises at least 1, 2, 3, 4, or 5’ ITRs. [0272] In some embodiments, the recombinant polynucleotide further comprises a 3’ inverted terminal repeat (3’ ITR). The 3’ ITR may be selected based on a vector used to deliver the recombinant polynucleotide. In some embodiments, the 3’ ITR may be an AAV 3’ ITR (e.g., an AAV53’ ITR, an AAV13’ ITR, an AAV23’ ITR, an AAV93’ ITR, or a PhP.eB 3’ ITR). The 3’ ITR may comprise at least 80% sequence identity to SEQ ID NO: 308. The 3’ ITR may comprise at least 85% sequence identity to SEQ ID NO: 308. The 3’ ITR may comprise at least 90% sequence identity to SEQ ID NO: 308. The 3’ ITR may comprise at least 95% sequence identity to SEQ ID NO: 308. The 3’ ITR may comprise at least 96% sequence identity to SEQ ID NO: 308. The 3’ ITR may comprise at least 97% sequence identity to SEQ ID NO: 308. The 3’ ITR may comprise at least 98% sequence identity to SEQ ID NO: 308. The 3’ ITR may comprise at least 99% sequence identity to SEQ ID NO: 308. The 3’ ITR may comprise 100% sequence identity to SEQ ID NO: 308. In some embodiments, the 3’ ITR is downstream of the promoter in the recombinant polynucleotide. In some embodiments the 3’ ITR is downstream of -124- ^{Docket No. 421688-718021 (718WO1)} the payload sequence. In some embodiments, the recombinant polynucleotide comprises at least 1, 2, 3, 4, or 3’ ITRs. [0273] In some embodiments, a recombinant polynucleotide includes one or more cloning sites. A cloning site may include a restriction site that may be specifically cut by a restriction enzyme. In some embodiments, a cloning site is a multiple cloning site comprising multiple restriction sites (e.g., from 2 to 20 restriction sites). A cloning site may be included between sequence elements within a recombinant polynucleotide (e.g., between a coding sequence and an additional element, between a coding sequence and a promoter, between a promoter and an additional element, between two additional elements, or combinations thereof). A cloning site can comprise a restriction enzyme cut site (also referred to as a “cut site” or a “restriction site”). Examples of cloning sites that may be included in a recombinant polynucleotide of the present disclosure are a HindIII cut site, a Xbal cut site, a NotI cut site, a SalI cut site, a PstI cut site, and combinations thereof. In some embodiments, a recombinant polynucleotide includes a cloning site between a progranulin coding sequence and a post-transcriptional regulatory element. For example, a recombinant polynucleotide includes a HindIII cut site between a payload sequence (e.g., SEQ ID NO: 350) and a WPRE3 post-transcriptional regulatory element (e.g., SEQ ID NO: 288). In some embodiments, a recombinant polynucleotide includes a cloning site between a post-transcriptional regulatory element and a polyadenylation site. For example, a recombinant polynucleotide includes a XbalI cut site between a WPRE3 post-transcriptional regulatory element (e.g., SEQ ID NO: 288) and a rabbit beta globin polyadenylation site (e.g., SEQ ID NO: 299). In some embodiments, a recombinant polynucleotide includes a cloning site between a polyadenylation site and a transcriptional pause site. For example, a recombinant polynucleotide includes a NotI cut site between a rabbit beta globin polyadenylation site (e.g., SEQ ID NO: 299) and a transcriptional pause site (e.g., SEQ ID NO: 311). In some embodiments, a recombinant polynucleotide includes a cloning site between a transcriptional pause site and a 3’ inverted terminal repeat. For example, a recombinant polynucleotide includes a SalI cut site and a PstI cut site between a transcriptional pause site (e.g., SEQ ID NO: 311) and a 3’ inverted terminal repeat (e.g., SEQ ID NO: 208). Recombinant Polynucleotides [0274] A recombinant polynucleotide may comprise a payload sequence (e.g., a transgene encoding a protein) operably linked to a core promoter (e.g., any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366) and an enhancer (e.g., a CNS-enhancer of any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385 or a liver-enhancer of SEQ ID NO: 362 or SEQ ID NO: 386). The -125- ^{Docket No. 421688-718021 (718WO1)} recombinant polynucleotide may encode for expression of a protein or polynucleotide encoded by payload (e.g., a therapeutic protein or a therapeutic polynucleotide). The recombinant polynucleotide can comprise a polynucleotide cassette coding for expression of a coding sequence, also referred to as an “expression cassette”. An expression cassette can comprise a coding sequence (e.g., a progranulin coding sequence) and one or more regulatory sequences (e.g., a promoter, a 5’ UTR, a post-transcriptional regulatory element, a polyadenylation signal, or combinations thereof) operably linked to the coding sequence to regulate transcription of the coding sequence. The core promoter and the enhancer may regulate expression of the payload sequence. The recombinant polynucleotide may include one or more additional elements (e.g., a post-transcriptional regulatory element, a polyadenylation signal, a transcriptional pause site, a neuron-restrictive silencer element, a CCCTC-binding factor sequence, a 5’ untranslated region, a 3’ untranslated region, a 5’ stuffer sequence, or combinations thereof). For example, the recombinant polynucleotide comprises a post-transcriptional regulatory element (e.g., a WPRE3 of SEQ ID NO: 288), a polyadenylation signal (e.g., a polyadenylation signal of SEQ ID NO: 299), and a transcriptional pause site (e.g., a transcriptional pause site of SEQ ID NO: 311). Examples of recombinant polynucleotide sequences comprising a payload encoding progranulin are provided in TABLE 6. TABLE 6 – Exemplary Recombinant Polynucleotides SEQ ID NO: Sequence SEQ ID NO: TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGG 312 GCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGA GTGGCCAACTCCATCACTAGGGGTTCCTGGATCCCTCGAGACGCGTCAATTGCCTAGGA GCTCCCCAAACCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGAGAGCTCAGCACA GATGATGCTCCAGTTGCTTAGCAACTAATGGTTTCCATGGAGACCGCAAAGCACAGCCT CCAGAGCAGCCAGTGAGCAGCTCGGCAGGGCAGGGAGAAGACGCAACTCCCTAGAGGG TATATAAAGGAAGCTCGACTTCCAGCTTGGCATTCCGGGCTAGCGCCGCCACCATGTGG ACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCAGA TGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCT GCCGTCCCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGC CAGGTTGATGCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCC AGTTGCTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACG GGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCG TGGGTGCCATCCAGTGCCCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTG TTATGGTCGATGGCTCCTGGGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACA GGGTGCACTGCTGTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACAC CCACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGT GGCCTTGTCCAGCTCGGTCATGTGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTAC CTGCTGTGAGCTGCCCAGTGGGAAGTATGGCTGCTGCCCAATGCCCAACGCCACCTGCT GCTCCGATCACCTGCACTGCTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAG TGCCTCTCCAAGGAGAACGCTACCACGGACCTCCTCACTAAGCTGCCTGCGCACACAGT GGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAGATGGCTATACCTGCTGCCGTC TACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCCAGGCTGTGTGCTGTGAGGACCAC ATACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCAGAAGGGTACCTGTGAACAGGG GCCCCACCAGGTGCCCTGGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCAC AAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCCTCCGATACCT GCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAGGCTGTCTGCTGC -126- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO: Sequence TCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGGGCAGTGTCA GCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCCCGCCGGGCTTCCTTAT CCCACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTGC TGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGA GGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGATCCTGCG AGAAGGAAGTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGTGGGT GTGAAGGACGTGGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCG AGACAACCGACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATC GGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGC AGGGAGGCCCCGCGCTGGGACGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTG AAAGCTTATCGAATTCCGCTCGAGATAATCAACCTCTGGATTACAAAATTTGTGAAAGA TTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGC CTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTG GTTAGTTCTTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGC TCGGCTGTTGGGCACTGACAATTCCGTGGTGTTTATTTGTGAAATTTGTGATGCTATTGC TTTATTTGTAACCATCTATCTAGAAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTT GGAATTTTTTGTGTCTCTCAGCGGCCGCAATAAAATATCTTTATTTTCATTACATCTGTGT GTTGGTTTTTTGTGTGAATCGATAGTACTAACATACGCTCTCCATCAAAACAAAACGAAA CAAAACAAACTAGCAAAATAGGCTGTCCCCAGTGCAAGTGCAGGTGCCAGAACATTTCT CTGTCGACCTGCAGAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCG CTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGG CCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAA [0275] In some embodiments, the recombinant polynucleotide comprises a CNS-enhancer (e.g., SEQ ID NO: 4), a minP variant core promoter (e.g., SEQ ID NO: 95), a payload encoding a progranulin protein (e.g., encoding a protein of SEQ ID NO: 352), a post-transcriptional regulator element (e.g., a WPRE3 of SEQ ID NO: 288), a polyadenylation signal (e.g., SEQ ID NO: 299), and a transcriptional pause site (e.g., SEQ ID NO: 311). In some embodiments, the recombinant polynucleotide comprises a CNS-enhancer (e.g., SEQ ID NO: 4), a minP variant core promoter (e.g., SEQ ID NO: 95), a payload encoding a progranulin protein (e.g., encoding a protein of SEQ ID NO: 352), a post-transcriptional regulator element (e.g., a WPRE3 of SEQ ID NO: 288), a polyadenylation signal (e.g., SEQ ID NO: 299), and a transcriptional pause site (e.g., SEQ ID NO: 311). In some embodiments, the recombinant polynucleotide further comprises a 5’ stuffer sequence (e.g., SEQ ID NO: 309). In some embodiments, the recombinant polynucleotide comprises a 5’ untranslated region. The 5’ untranslated region may comprise a sequence that overlaps with the promoter (e.g., SEQ ID NO: 310 which includes the 3’ 7 nucleotides of a minP variant core promoter). The 5’ untranslated region can comprise a Kozak sequence (e.g., SEQ ID NO: 354) and can further comprise additional nucleotides 5’ of the Kozak sequence (e.g., comprising 7 nucleotides overlapping the 3’ end of the core promoter and comprising additional nucleotides between the 3’ end of the core promoter and the Kozak sequence). The 5’ untranslated region can comprise a sequence of SEQ ID NO: 353 and can further comprise a region 5’ of SEQ ID NO: 353 that overlaps the core promoter (e.g., comprising 7 nucleotides overlapping the 3’ end of the core promoter). In some embodiments, the recombinant polynucleotide comprises a CNS-enhancer (e.g., SEQ ID NO: 4), a minP -127- ^{Docket No. 421688-718021 (718WO1)} variant core promoter (e.g., SEQ ID NO: 95), a payload encoding a progranulin protein (e.g., encoding a protein of SEQ ID NO: 350), a WPRE3 (e.g., SEQ ID NO: 288), a polyadenylation signal (e.g., SEQ ID NO: 299), and a transcriptional pause site (e.g., SEQ ID NO: 311). In some embodiments, the recombinant polynucleotide comprises SEQ ID NO: 4, SEQ ID NO: 95, SEQ ID NO: 350, SEQ ID NO: 288, SEQ ID NO: 299, and SEQ ID NO: 311. In some embodiments, the recombinant polynucleotide further comprises SEQ ID NO: 309. In some embodiments, the recombinant polynucleotide comprises SEQ ID NO: 310 which includes the 3’ 7 nucleotides of a minP variant core promoter (e.g., SEQ ID NO: 95). In some embodiments, the recombinant polynucleotide comprises SEQ ID NO: 353. In some embodiments, the recombinant polynucleotide comprises SEQ ID NO: 4, SEQ ID NO: 95, SEQ ID NO: 353, SEQ ID NO: 350, SEQ ID NO: 288, SEQ ID NO: 299, and SEQ ID NO: 311. In some embodiments, a recombinant polynucleotide may comprise, from 5’ to 3’, a 5’ stuffer sequence of SEQ ID NO: 309, a CNS-enhancer of SEQ ID NO: 4, a minP variant core promoter of SEQ ID NO: 95, a 5’ untranslated region of SEQ ID NO: 310 (which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a progranulin coding sequence of SEQ ID NO: 350 (comprising a sequence of SEQ ID NO: 358 encoding a progranulin signal peptide and a sequence of SEQ ID NO: 359), a HindIII restriction site, a WPRE3 post-transcriptional regulatory element of SEQ ID NO: 288, a XbalI restriction site, a polyadenylation signal of SEQ ID NO: 299, a NotI restriction site, a transcriptional pause site of SEQ ID NO: 311, a SalI restriction site, and a PstI restriction site. For example, the recombinant polynucleotide comprises a sequence of SEQ ID NO: 312. [0276] In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4 and (ii) SEQ ID NO 95. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; and (iii) SEQ ID NO: 350. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; and (iv) SEQ ID NO: 288. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; and (iv) SEQ ID NO: 299. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; (iv) SEQ ID NO: 288; and (v) SEQ ID NO: 299. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; and (iv) SEQ ID NO: 311. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; (iv) SEQ ID NO: 288; (v) SEQ ID NO: 299; and (vi) SEQ ID NO: 311. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) -128- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO 95; (iii) SEQ ID NO: 353; (iv) SEQ ID NO: 350; (v) SEQ ID NO: 288; (vi) SEQ ID NO: 299; and (vii) SEQ ID NO: 311. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; and (iii) SEQ ID NO: 353. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; and (v) SEQ ID NO: 350. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; and (vii) SEQ ID NO: 299. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; and (vi) SEQ ID NO: 311. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; (vii) SEQ ID NO: 299; and (viii) SEQ ID NO: 311. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 309; (iii) SEQ ID NO: 4; (iv) SEQ ID NO 95; (v) SEQ ID NO: 353; (vi) SEQ ID NO: 350; (vii) SEQ ID NO: 288; (viii) SEQ ID NO: 299; (ix) SEQ ID NO: 311; and (x) SEQ ID NO: 308. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; and (iii) SEQ ID NO: 308. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; and (iv) SEQ ID NO: 308. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; and (vi) SEQ ID NO: 308. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; (vii) SEQ ID NO: 299; and (viii) SEQ ID NO: 308. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 311; and (vii) SEQ ID NO: 308. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; (vii) SEQ ID NO: 299; (viii) SEQ ID NO: 311; and (ix) SEQ ID NO: 308. In some embodiments, the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 309; (iii) SEQ ID NO: 4; (iv) SEQ ID NO 95; (v) SEQ ID NO: 353; (vi) SEQ ID NO: 350; (vii) SEQ ID NO: 288; (viii) SEQ ID NO: 299; (ix) SEQ ID NO: 311; and (x) SEQ ID NO: 308. -129- ^{Docket No. 421688-718021 (718WO1)} [0277] In some embodiments, a recombinant polynucleotide (e.g., a recombinant polynucleotide of SEQ ID NO: 312, as shown in FIG.36) may comprise, from 5’ to 3’, a 5’ ITR (e.g., SEQ ID NO: 307), a 5’ stuffer sequence (e.g., SEQ ID NO: 309), a CNS-enhancer (e.g., SEQ ID NO: 4), a minP variant core promoter (e.g., SEQ ID NO: 95), a 5’ UTR (e.g., SEQ ID NO: 310 which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a coding sequence (e.g., SEQ ID NO: 350), a post- transcriptional regulatory element (e.g., SEQ ID NO: 288), a polyA signal (e.g., SEQ ID NO: 299), a transcriptional pause site (e.g., SEQ ID NO: 311), and a 3’ ITR (e.g., SEQ ID NO: 308). In some embodiments, a recombinant polynucleotide may comprise, from 5’ to 3’, SEQ ID NO: 307, SEQ ID NO: 309, SEQ ID NO: 4, SEQ ID NO: 95, SEQ ID NO: 310 which comprises 7 nucleotides of the 3’ end of the core promoter of SEQ ID NO: 95 and a Kozak sequence of SEQ ID NO: 354, SEQ ID NO: 350, a post-transcriptional regulatory element (e.g., SEQ ID NO: 288), a polyA signal (e.g., SEQ ID NO: 299, SEQ ID NO: 311, and SEQ ID NO: 308. In some embodiments, a recombinant polynucleotide may comprise, from 5’ to 3’, SEQ ID NO: 307, SEQ ID NO: 309, SEQ ID NO: 4, SEQ ID NO: 95, SEQ ID NO: 353, SEQ ID NO: 350, SEQ ID NO: 288, SEQ ID NO: 299, SEQ ID NO: 311, and SEQ ID NO: 308. In some embodiments, a recombinant polynucleotide may comprise a 5’ stuffer sequence of SEQ ID NO: 309, a CNS- enhancer of SEQ ID NO: 4, a minP variant core promoter of SEQ ID NO: 95, a 5’ untranslated region of SEQ ID NO: 310 (which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a progranulin coding sequence of SEQ ID NO: 350 (comprising a sequence of SEQ ID NO: 358 encoding a progranulin signal peptide and a sequence of SEQ ID NO: 359), a HindIII restriction site, a WPRE3 post-transcriptional regulatory element of SEQ ID NO: 288, a XbalI restriction site, a polyadenylation signal of SEQ ID NO: 299, a NotI restriction site, a transcriptional pause site of SEQ ID NO: 311, a SalI restriction site, and a PstI restriction site. In some embodiments, a recombinant polynucleotide may comprise a 5’ inverted terminal repeat of SEQ ID NO: 307, a 5’ stuffer sequence of SEQ ID NO: 309, a CNS-enhancer of SEQ ID NO: 4, a minP variant core promoter of SEQ ID NO: 95, a 5’ untranslated region of SEQ ID NO: 310 (which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a progranulin coding sequence of SEQ ID NO: 350 (comprising a sequence of SEQ ID NO: 358 encoding a progranulin signal peptide and a sequence of SEQ ID NO: 359), a HindIII restriction site, a WPRE3 post-transcriptional regulatory element of SEQ ID NO: 288, a XbalI restriction site, a polyadenylation signal of SEQ ID NO: 299, a NotI restriction site, a transcriptional pause site of SEQ ID NO: 311, a SalI restriction site, a PstI restriction site, and a 3’ inverted terminal repeat of SEQ ID NO: 308. -130- ^{Docket No. 421688-718021 (718WO1)} [0278] The recombinant polynucleotide may comprise at least 80% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 85% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 90% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 95% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 96% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 97% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 98% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 99% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 100% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise a sequence of SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 80% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 85% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 90% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 95% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about about 96% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 97% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 98% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 99% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 100% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise a sequence of SEQ ID NO: 312. [0279] The recombinant polynucleotide may comprise about 80% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 85% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 90% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 95% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 96% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 97% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 98% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 99% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 100% sequence identity to SEQ ID NO: 312. [0280] The recombinant polynucleotide may comprise 80% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 85% sequence identity to SEQ ID NO: 312. -131- ^{Docket No. 421688-718021 (718WO1)} The recombinant polynucleotide may comprise 90% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 95% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 96% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 97% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 98% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 99% sequence identity to SEQ ID NO: 312. [0281] In some embodiments, it is advantageous to include small components (e.g., components with relatively short polynucleotide sequences) in a recombinant polynucleotide. Since delivery vectors (e.g., viral vectors or plasmids) can have a limited polynucleotide capacity, inclusion of small components rather than larger components (e.g., components with longer polynucleotide sequences) in a recombinant polynucleotide for delivery by the vector can leave room in the vector for additional elements. For example, inclusion of small components in a recombinant polynucleotide delivered by a vector can leave room in the vector for an additional coding sequence, an additional regulatory sequence, or an additional expression cassette. An example of a small promoter is a minP variant core promoter (e.g., SEQ ID NO: 95). An example of a small post-transcriptional regulatory element is a WPRE3 (e.g., SEQ ID NO: 288). Particular Recombinant Polynucleotides of the Present Invention [0282] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 1, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0283] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to -132- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO: 2, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0284] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 3, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0285] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0286] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 5, or a reverse complement thereof; and -133- ^{Docket No. 421688-718021 (718WO1)} a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0287] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 6, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0288] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 7, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0289] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 8, or a reverse complement thereof; and a core promoter; -134- ^{Docket No. 421688-718021 (718WO1)} optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0290] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 9, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0291] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 10, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0292] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 11, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of -135- ^{Docket No. 421688-718021 (718WO1)} the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0293] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 12, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0294] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 13, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0295] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 14, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of -136- ^{Docket No. 421688-718021 (718WO1)} the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0296] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 15, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0297] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 16, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0298] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 17, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of -137- ^{Docket No. 421688-718021 (718WO1)} the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0299] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 18, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0300] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 19, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0301] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 20, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of -138- ^{Docket No. 421688-718021 (718WO1)} the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0302] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 360, or a reverse complement thereof; and a core promoter; optionally further comprising a payload, wherein the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. The coding sequence can encode a progranulin. [0303] In the embodiments described above, the core promoter can comprise at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0304] In the embodiments described above, the coding sequence encoding a progranulin can comprise at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0305] In the embodiments described above, the recombinant polynucleotide can further comprise additional elements as disclosed herein. [0306] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 1, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0307] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about -139- ^{Docket No. 421688-718021 (718WO1)} 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 2, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0308] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 3, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0309] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0310] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 5, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. -140- ^{Docket No. 421688-718021 (718WO1)} [0311] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 6, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0312] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 7, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0313] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 8, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0314] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 9, or a reverse complement thereof; and -141- ^{Docket No. 421688-718021 (718WO1)} a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0315] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 10, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0316] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 11, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0317] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 12, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0318] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at -142- ^{Docket No. 421688-718021 (718WO1)} least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 13, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0319] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 14, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0320] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 15, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0321] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 16, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0322] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about -143- ^{Docket No. 421688-718021 (718WO1)} 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 17, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0323] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 18, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0324] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 19, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0325] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 20, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. -144- ^{Docket No. 421688-718021 (718WO1)} [0326] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 360, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95. [0327] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 1, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0328] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 2, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. -145- ^{Docket No. 421688-718021 (718WO1)} [0329] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 3, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0330] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0331] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 5, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a -146- ^{Docket No. 421688-718021 (718WO1)} progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0332] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 6, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0333] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 7, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0334] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 8, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least -147- ^{Docket No. 421688-718021 (718WO1)} 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0335] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 9, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0336] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 10, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0337] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to -148- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO: 11, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0338] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 12, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0339] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 13, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0340] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least -149- ^{Docket No. 421688-718021 (718WO1)} about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 14, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0341] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 15, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0342] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 16, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0343] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: -150- ^{Docket No. 421688-718021 (718WO1)} an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 17, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0344] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 18, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0345] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 19, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. -151- ^{Docket No. 421688-718021 (718WO1)} [0346] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 20, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0347] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 360, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0348] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 1, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a -152- ^{Docket No. 421688-718021 (718WO1)} progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0349] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 2, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0350] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 3, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0351] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a -153- ^{Docket No. 421688-718021 (718WO1)} progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0352] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 5, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0353] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 6, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0354] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 7, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a -154- ^{Docket No. 421688-718021 (718WO1)} progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0355] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 8, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0356] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 9, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0357] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 10, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a -155- ^{Docket No. 421688-718021 (718WO1)} progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0358] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 11, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0359] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 12, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0360] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 13, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a -156- ^{Docket No. 421688-718021 (718WO1)} progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0361] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 14, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0362] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 15, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0363] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 16, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a -157- ^{Docket No. 421688-718021 (718WO1)} progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0364] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 17, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0365] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 18, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0366] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 19, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a -158- ^{Docket No. 421688-718021 (718WO1)} progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0367] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 20, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0368] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 360, or a reverse complement thereof; and a core promoter; and further comprising a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0369] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 1, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. -159- ^{Docket No. 421688-718021 (718WO1)} [0370] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 2, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0371] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 3, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0372] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0373] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least -160- ^{Docket No. 421688-718021 (718WO1)} about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 5, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0374] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 6, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0375] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 7, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0376] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 8, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least -161- ^{Docket No. 421688-718021 (718WO1)} 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0377] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 9, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0378] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 10, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0379] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 11, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0380] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: -162- ^{Docket No. 421688-718021 (718WO1)} an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 12, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0381] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 13, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0382] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 14, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0383] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to -163- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO: 15, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0384] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 16, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0385] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 17, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0386] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 18, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. -164- ^{Docket No. 421688-718021 (718WO1)} [0387] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 19, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0388] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 20, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0389] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 360, or a reverse complement thereof; and a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and further comprising a payload. [0390] In some embodiments, the recombinant polynucleotide further comprises additional elements as disclosed herein. [0391] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: -165- ^{Docket No. 421688-718021 (718WO1)} an enhancer comprising a sequence having at least about 70%, at least about 72%, at least about 75%, at least about 78%, at least about 80%, at least about 82%, at least about 85%, at least about 87%, at least about 90%, at least about 92%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; a core promoter comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95; and a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity SEQ ID NO: 350. [0392] A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising the sequence of SEQ ID NO: 4, or a reverse complement thereof; a core promoter comprising the sequence of SEQ ID NO: 95; and a payload, wherein the payload comprises a coding sequence encoding a progranulin comprising the sequence of SEQ ID NO: 350. [0393] Additional recombinant polynucleotides of the present disclosure are provided in TABLE 7. TABLE 7 – Recombinant Polynucleotides Recombinant Enhancer Core Promoter Optional payload Polynucleotide A SEQ ID NO: 1 SEQ ID NO: 95 SEQ ID NO: 350 B SEQ ID NO: 2 SEQ ID NO: 95 SEQ ID NO: 350 C SEQ ID NO: 3 SEQ ID NO: 95 SEQ ID NO: 350 D SEQ ID NO: 4 SEQ ID NO: 95 SEQ ID NO: 350 E SEQ ID NO: 5 SEQ ID NO: 95 SEQ ID NO: 350 F SEQ ID NO: 6 SEQ ID NO: 95 SEQ ID NO: 350 G SEQ ID NO: 7 SEQ ID NO: 95 SEQ ID NO: 350 H SEQ ID NO: 8 SEQ ID NO: 95 SEQ ID NO: 350 I SEQ ID NO: 9 SEQ ID NO: 95 SEQ ID NO: 350 -166- ^{Docket No. 421688-718021 (718WO1)} J SEQ ID NO: 10 SEQ ID NO: 95 SEQ ID NO: 350 K SEQ ID NO: 11 SEQ ID NO: 95 SEQ ID NO: 350 L SEQ ID NO: 12 SEQ ID NO: 95 SEQ ID NO: 350 M SEQ ID NO: 13 SEQ ID NO: 95 SEQ ID NO: 350 N SEQ ID NO: 14 SEQ ID NO: 95 SEQ ID NO: 350 O SEQ ID NO: 15 SEQ ID NO: 95 SEQ ID NO: 350 P SEQ ID NO: 16 SEQ ID NO: 95 SEQ ID NO: 350 Q SEQ ID NO: 17 SEQ ID NO: 95 SEQ ID NO: 350 R SEQ ID NO: 18 SEQ ID NO: 95 SEQ ID NO: 350 S SEQ ID NO: 19 SEQ ID NO: 95 SEQ ID NO: 350 T SEQ ID NO: 20 SEQ ID NO: 95 SEQ ID NO: 350 U SEQ ID NO: 360 SEQ ID NO: 95 SEQ ID NO: 350 Recombinant Vectors [0394] In some embodiments, the polynucleotide of the present disclosure is introduced into a subject via a recombinant vector. In some embodiments the vector is a plasmid, a viral vector, an expression cassette, or a transformed cell. The compact size of the enhancers described herein may facilitate incorporation into a recombinant vector, allowing for inclusion of larger payloads. [0395] In some embodiments, the viral vector is an adenoviral vector, an adeno-associated viral vector, or a lentiviral vector. Adeno-associated virus (AAV) vectors include vectors derived from any AAV serotype, including, but not limited to AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV-DJ, AAV-DJ/8, AAV-DJ/9, AAV1/2, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh43, AAV.Rh74, AAV.v66, AAV.Oligo001, AAV.SCH9, AAV.r3.45, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PhP.eB, AAV.PhP.V1, AAV.PHP.B, AAV.PhB.C1, AAV.PhB.C2, AAV.PhB.C3, AAV.PhB.C6, AAV.cy5, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAV.HSC17, and AAVhu68. -167- ^{Docket No. 421688-718021 (718WO1)} [0396] In some embodiments, a polynucleotide is introduced into a subject by non-viral vector systems. In some embodiments, cationic lipids, polymers, hydrodynamic injection and/or ultrasound may be used in delivering a polynucleotide to a subject in the absence of virus. [0397] In some examples, the vector may be a eukaryotic vector, a prokaryotic vector (e.g., a bacterial vector) a viral vector, or any combination thereof. In some examples, the vector may be a viral vector. In some embodiments, the viral vector may be a retroviral vector, an adenoviral vector, an adeno-associated viral (AAV) vector, an alphavirus vector, a lentivirus vector (e.g., human or porcine), a Herpes virus vector, an Epstein-Barr virus vector, an SV40 virus vectors, a pox virus vector, or a combination thereof. In some embodiments, the viral vector may be a recombinant vector, a hybrid vector, a chimeric vector, a self-complementary vector, a single- stranded vector, or any combination thereof. [0398] In some embodiments, the viral vector may be an adeno-associated virus (AAV). In some embodiments, the AAV may be any AAV known in the art. In some embodiments, the viral vector may be of a specific serotype. In some embodiments, the viral vector may be an AAV1 serotype, AAV2 serotype, AAV3 serotype, AAV4 serotype, AAV5 serotype, AAV6 serotype, AAV7 serotype, AAV8 serotype, AAV9 serotype, AAV10 serotype, AAV11 serotype, AAV 12 serotype, AAV13 serotype, AAV14 serotype, AAV15 serotype, AAV16 serotype, AAV-DJ serotype, AAV-DJ/8 serotype, AAV-DJ/9 serotype, AAV1/2 serotype, AAV.rh8 serotype, AAV.rh10 serotype, AAV.rh20 serotype, AAV.rh39 serotype, AAV.Rh43 serotype, AAV.Rh74 serotype, AAV.v66 serotype, AAV.Oligo001 serotype, AAV.SCH9 serotype, AAV.r3.45 serotype, AAV.RHM4-1 serotype, AAV.hu37 serotype, AAV.Anc80 serotype, AAV.Anc80L65 serotype, AAV.7m8 serotype, AAV.PhP.eB serotype, AAV.PhP.V1 serotype, AAV.PHP.B serotype, AAV.PhB.C1 serotype, AAV.PhB.C2 serotype, AAV.PhB.C3 serotype, AAV.PhB.C6 serotype, AAV.cy5 serotype, AAV2.5 serotype, AAV2tYF serotype, AAV3B serotype, AAV.LK03 serotype, AAV.HSC1 serotype, AAV.HSC2 serotype, AAV.HSC3 serotype, AAV.HSC4 serotype, AAV.HSC5 serotype, AAV.HSC6 serotype, AAV.HSC7 serotype, AAV.HSC8 serotype, AAV.HSC9 serotype, AAV.HSC10 serotype, AAV.HSC11 serotype, AAV.HSC12 serotype, AAV.HSC13 serotype, AAV.HSC14 serotype, AAV.HSC15 serotype, AAV.HSC16 serotype, AAV.HSC17 serotype, or AAVhu68 serotype, a derivative of any of these serotypes, or any combination thereof. [0399] In some embodiments, the AAV vector may be a recombinant vector, a hybrid AAV vector, a chimeric AAV vector, a self-complementary AAV (scAAV) vector, a single-stranded AAV, or any combination thereof. -168- ^{Docket No. 421688-718021 (718WO1)} [0400] In some embodiments, the AAV vector may be a recombinant AAV (rAAV) vector or engineered AAV vector. Methods of producing recombinant AAV vectors may be known in the art and generally involve, in some cases, introducing into a producer cell line: (1) DNA necessary for AAV replication and synthesis of an AAV capsid, (b) one or more helper constructs comprising the viral functions missing from the AAV vector, (c) a helper virus, and (d) the plasmid construct containing the genome of the AAV vector, e.g., ITRs, promoter and transgene sequences, etc. In some examples, the viral vectors described herein may be engineered through synthetic or other suitable means by references to published sequences, such as those that may be available in the literature. For example, the genomic and protein sequences of various serotypes of AAV, as well as the sequences of the native terminal repeats (TRs), Rep proteins, and capsid subunits may be known in the art and may be found in the literature or in public databases such as GenBank or Protein Data Bank (PDB). [0401] An AAV vector may be assembled from one or more viral capsid proteins (VP). Viral capsid protein is referred to as AAV5 VP1 when referencing AAV5 VP1 positional notation. In all cases, viral capsid sequences and mutations disclosed herein should be understood as pertaining to all isoforms of the capsid protein (VP1, VP2, and VP3), as a mixture of these isoforms assemble to form virions. The positional amino acid residue designations “581 to 589” are relative to the translational start of the AAV5 VP1 polypeptide and should be adjusted accordingly to the relative start sites of AAV5 VP2 and AAV5 VP3. It should be understood that the present disclosure, when describing any particular VP1 sequence with mutations at particular amino acid residue positions, necessarily also encompasses corresponding mutations in VP2 and VP3. For example, any consensus sequence or specific sequence of an AAV5 VP1 capsid protein having one or more mutations in the 581-589 region, corresponding to amino acid residues 581 to 589 of AAV5 VP1, also encompasses AAV5 VP2 and AAV5 VP3 capsid proteins having said one or more mutations in an amino acid residue region in VP2 and VP3 corresponding to the amino acid residues of the VP1581 to 589 region. For example, the amino acid residues of the 581 to 589 region of AAV5 VP1 (SEQ ID NO: 313; MSFVDHPPDWLEEVGEGLREFLGLEAGPPKPKPNQQHQDQARGLVLPGYNYLGPGNGL DRGEPVNRADEVAREHDISYNEQLEAGDNPYLKYNHADAEFQEKLADDTSFGGNLGK AVFQAKKRVLEPFGLVEEGAKTAPTGKRIDDHFPKRKKARTEEDSKPSTSSDAEAGPSGS QQLQIPAQPASSLGADTMSAGGGGPLGDNNQGADGVGNASGDWHCDSTWMGDRVVT KSTRTWVLPSYNNHQYREIKSGSVDGSNANAYFGYSTPWGYFDFNRFHSHWSPRDWQ RLINNYWGFRPRSLRVKIFNIQVKEVTVQDSTTTIANNLTSTVQVFTDDDYQLPYVVGN GTEGCLPAFPPQVFTLPQYGYATLNRDNTENPTERSSFFCLEYFPSKMLRTGNNFEFTYN FEEVPFHSSFAPSQNLFKLANPLVDQYLYRFVSTNNTGGVQFNKNLAGRYANTYKNWFP -169- ^{Docket No. 421688-718021 (718WO1)} GPMGRTQGWNLGSGVNRASVSAFATTNRMELEGASYQVPPQPNGMTNNLQGSNTYAL ENTMIFNSQPANPGTTATYLEGNMLITSESETQPVNRVAYNVGGQMATNNQSSTTAPATG TYNLQEIVPGSVWMERDVYLQGPIWAKIPETGAHFHPSPAMGGFGLKHPPPMMLIKNTP VPGNITSFSDVPVSSFITQYSTGQVTVEMEWELKKENSKRWNPEIQYTNNYNDPQFVDF APDSTGEYRTTRPIGTRYLTRPL) correspond to the amino acid residues of the 445 to 453 region of AAV5 VP2 (SEQ ID NO: 314; TAPTGKRIDDHFPKRKKARTEEDSKPSTSSDAEAGPSGSQQLQIPAQPASSLGADTMSAG GGGPLGDNNQGADGVGNASGDWHCDSTWMGDRVVTKSTRTWVLPSYNNHQYREIKS GSVDGSNANAYFGYSTPWGYFDFNRFHSHWSPRDWQRLINNYWGFRPRSLRVKIFNIQ VKEVTVQDSTTTIANNLTSTVQVFTDDDYQLPYVVGNGTEGCLPAFPPQVFTLPQYGYA TLNRDNTENPTERSSFFCLEYFPSKMLRTGNNFEFTYNFEEVPFHSSFAPSQNLFKLANPL VDQYLYRFVSTNNTGGVQFNKNLAGRYANTYKNWFPGPMGRTQGWNLGSGVNRASV SAFATTNRMELEGASYQVPPQPNGMTNNLQGSNTYALENTMIFNSQPANPGTTATYLEG NMLITSESETQPVNRVAYNVGGQMATNNQSSTTAPATGTYNLQEIVPGSVWMERDVYL QGPIWAKIPETGAHFHPSPAMGGFGLKHPPPMMLIKNTPVPGNITSFSDVPVSSFITQYST GQVTVEMEWELKKENSKRWNPEIQYTNNYNDPQFVDFAPDSTGEYRTTRPIGTRYLTRP L) and to the amino acid residues of 389 to 397 region of AAV5 VP3 (SEQ ID NO: 315; MSAGGGGPLGDNNQGADGVGNASGDWHCDSTWMGDRVVTKSTRTWVLPSYNNHQY REIKSGSVDGSNANAYFGYSTPWGYFDFNRFHSHWSPRDWQRLINNYWGFRPRSLRVK IFNIQVKEVTVQDSTTTIANNLTSTVQVFTDDDYQLPYVVGNGTEGCLPAFPPQVFTLPQ YGYATLNRDNTENPTERSSFFCLEYFPSKMLRTGNNFEFTYNFEEVPFHSSFAPSQNLFKL ANPLVDQYLYRFVSTNNTGGVQFNKNLAGRYANTYKNWFPGPMGRTQGWNLGSGVN RASVSAFATTNRMELEGASYQVPPQPNGMTNNLQGSNTYALENTMIFNSQPANPGTTAT YLEGNMLITSESETQPVNRVAYNVGGQMATNNQSSTTAPATGTYNLQEIVPGSVWMERD VYLQGPIWAKIPETGAHFHPSPAMGGFGLKHPPPMMLIKNTPVPGNITSFSDVPVSSFITQ YSTGQVTVEMEWELKKENSKRWNPEIQYTNNYNDPQFVDFAPDSTGEYRTTRPIGTRYL TRPL). As used herein, “wild type AAV5” or “wild type AAV5 capsid polypeptide” refers to an AAV5 VP1 capsid polypeptide of SEQ ID NO: 313, an AAV5 VP2 capsid polypeptide of SEQ ID NO: 314, an AAV5 VP3 capsid polypeptide of SEQ ID NO: 315, or a combination thereof. Also as used herein, a “wild type 581-589 region” refers to a 581 to 589 region of AAV5 VP1 having a sequence of ATGTYNLQE (SEQ ID NO: 317). [0402] As used herein, “581-589 region” refers to a region or fragment of AAV5 VP1 corresponding to amino acid residues 581 to 589 relative to the translational start of the AAV5 VP1 polypeptide. A 581-589 region comprising at least one mutation relative to a wild type 581- 589 region sequence (e.g., a 581-589 region of a wild type AAV5 VP1 capsid polypeptide) may -170- ^{Docket No. 421688-718021 (718WO1)} also be referred to as a “variant region” or a “variant 581-589 region.” The 581-589 region corresponds to amino acid residues 445 to 453 of AAV5 VP2 and to amino acid residues 389 to 397 of AAV5 VP3. The 581-589 region may confer tissue tropism to an AAV, and defined variants may be engineered to confer tissue tropism to an rAAV formed from viral capsid polypeptides (VP1, VP2, and VP3) comprising the 581-589 region. The AAV5 VP1 with a generalized 581-589 region is provided in SEQ ID NO: 316 (MSFVDHPPDWLEEVGEGLREFLGLEAGPPKPKPNQQHQDQARGLVLPGYNYLGPGNG LDRGEPVNRADEVAREHDISYNEQLEAGDNPYLKYNHADAEFQEKLADDTSFGGNLGK AVFQAKKRVLEPFGLVEEGAKTAPTGKRIDDHFPKRKKARTEEDSKPSTSSDAEAGPSGS QQLQIPAQPASSLGADTMSAGGGGPLGDNNQGADGVGNASGDWHCDSTWMGDRVVT KSTRTWVLPSYNNHQYREIKSGSVDGSNANAYFGYSTPWGYFDFNRFHSHWSPRDWQ RLINNYWGFRPRSLRVKIFNIQVKEVTVQDSTTTIANNLTSTVQVFTDDDYQLPYVVGN GTEGCLPAFPPQVFTLPQYGYATLNRDNTENPTERSSFFCLEYFPSKMLRTGNNFEFTYN FEEVPFHSSFAPSQNLFKLANPLVDQYLYRFVSTNNTGGVQFNKNLAGRYANTYKNWFP GPMGRTQGWNLGSGVNRASVSAFATTNRMELEGASYQVPPQPNGMTNNLQGSNTYAL ENTMIFNSQPANPGTTATYLEGNMLITSESETQPVNRVAYNVGGQMATNNQSSTTAPX¹X ²X³X⁴X⁵X⁶X⁷X⁸X⁹IVPGSVWMERDVYLQGPIWAKIPETGAHFHPSPAMGGFGLKHPPPMM LIKNTPVPGNITSFSDVPVSSFITQYSTGQVTVEMEWELKKENSKRWNPEIQYTNNYNDP QFVDFAPDSTGEYRTTRPIGTRYLTRPL), in which the 581-589 region has a sequence of X¹X²X³X⁴X⁵X⁶X⁷X⁸X⁹; wherein X¹, X², X³, X⁴, X⁵, X⁶, X⁷, X⁸, and X⁹ are each independently selected from A, R, N, D, C, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y, and V. [0403] In some embodiments, an engineered adeno-associated virus (AAV) viral protein (VP) capsid polypeptide has an amino acid sequence at least 70% identical to an AAV5 VP capsid polypeptide (e.g., a VP capsid polypeptide of SEQ ID NO: 313, SEQ ID NO: 314, or SEQ ID NO: 315), wherein the engineered AAV5 VP capsid polypeptide has at least one substitution as compared to SEQ ID NO: 313 in the 581-589 region, corresponding to residue 581 to residue 589 of SEQ ID NO: 313, inclusive, wherein the capsid polypeptide is capable of assembling into a recombinant AAV5 virion (rAAV5). In some embodiments, the AAV5 VP capsid polypeptide comprises a variant 581-589 region (e.g., comprising one or more amino acid substitutions relative to SEQ ID NO: 313 in the region from residue 581 to residue 589, inclusive). The AAV5 VP capsid polypeptide may comprise a sequence of SEQ ID NO: 316, wherein the 581-589 region has a one or more mutations relative to the wild type AAV5 VP1 capsid polypeptide, wherein the one or more mutations confers tissue tropism (e.g., CNS tissue tropism). For example, an AAV5 VP capsid polypeptide may comprise a sequence of SEQ ID NO: 316, wherein the 581-589 region has a sequence of any one of SEQ ID NO: 320 – SEQ ID NO: 349. -171- ^{Docket No. 421688-718021 (718WO1)} In some embodiments, the 581-589 region confers tropism for a tissue of interest (e.g., CNS tissue). Examples of 581-589 region sequences that may be included in an engineered VP capsid polypeptide (e.g., an engineered AAV5 VP capsid polypeptide) are provided in TABLE 8. In some embodiments, a 581-589 region sequence provided in TABLE 8 may confer CNS tissue tropism on a rAAV assembled from engineered VP capsid polypeptides including the 581-589 region sequence. TABLE 8 – Exemplary 581-589 Region Sequences SEQ ID NO: Sequence SEQ ID NO: 320 AAGRFNYFG SEQ ID NO: 321 MDDICEFYA SEQ ID NO: 322 DAWCFISSY SEQ ID NO: 323 TANVYRSGQ SEQ ID NO: 324 TSHYITFTP SEQ ID NO: 325 DARVYRALD SEQ ID NO: 326 EAWSKLEQP SEQ ID NO: 327 LWGWTLQHQ SEQ ID NO: 328 QTAEFKRHQ SEQ ID NO: 329 LVGWTLQHV SEQ ID NO: 330 CATRFNIGG SEQ ID NO: 331 DAWLQLKDN SEQ ID NO: 332 QALMLTRQQ SEQ ID NO: 333 EAWMYHQFH SEQ ID NO: 334 AEDYWDLGA SEQ ID NO: 335 TAAFAYKYE SEQ ID NO: 336 DAWSYQCYH SEQ ID NO: 337 TAGRFNYFD SEQ ID NO: 338 QKGPHNMSE SEQ ID NO: 339 DAWQMLSGN SEQ ID NO: 340 ESWMKLEWQ SEQ ID NO: 341 DAWSVLQDK SEQ ID NO: 342 DSASPIMGM SEQ ID NO: 343 EEEWLNGWQ SEQ ID NO: 344 ITLASKSMR SEQ ID NO: 345 ICMSRTQMK -172- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO: Sequence SEQ ID NO: 346 DAWMMMWGS SEQ ID NO: 347 LRTPHNHGL SEQ ID NO: 348 YSGVRVTGY SEQ ID NO: 349 YWQSMLWQG [0404] In particular embodiments, the engineered adeno-associated virus (AAV) viral protein (VP) capsid polypeptide has an amino acid sequence at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% identical to an AAV5 VP capsid polypeptide (e.g., a VP capsid polypeptide of SEQ ID NO: 313, SEQ ID NO: 314, or SEQ ID NO: 315). [0405] In some embodiments, the AAV VP capsid polypeptides have an amino acid sequence of SEQ ID NO: 316, wherein X¹, X², X³, X⁴, X⁵, X⁶, X⁷, X⁸, and X⁹ are each independently selected from A, R, N, D, C, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y, and V. In some embodiments, the AAV VP capsid polypeptide has an amino acid sequence of SEQ ID NO: 316, wherein the X¹X²X³X⁴X⁵X⁶X⁷X⁸X⁹ portion corresponds to a sequence selected from any one of SEQ ID NO: 320 – SEQ ID NO: 349. [0406] In some embodiments, the 581-589 region of the engineered VP capsid polypeptide, corresponding to residues 581 to 589, inclusive, with reference to SEQ ID NO: 313, has a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NO: 320 – SEQ ID NO: 349. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 1 amino acid substitution relative to any one of SEQ ID NO: 320 – SEQ ID NO: 349. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 2 amino acid substitutions relative to any one of SEQ ID NO: 320 – SEQ ID NO: 349. In particular embodiments, the 581-589 region of the engineered VP capsid polypeptide has a sequence that is identical to any one of SEQ ID NO: 320 – SEQ ID NO: 349. [0407] In some embodiments, the 581-589 region of the engineered VP capsid polypeptide, corresponding to residues 581 to 589, inclusive, with reference to SEQ ID NO: 313, has a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 320. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 1 amino acid substitution relative to SEQ ID NO: 320. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide -173- ^{Docket No. 421688-718021 (718WO1)} comprises 2 amino acid substitutions relative to SEQ ID NO: 320. In particular embodiments, the 581-589 region of the engineered VP capsid polypeptide has a sequence that is identical to SEQ ID NO: 320. [0408] In some embodiments, the 581-589 region of the engineered VP capsid polypeptide, corresponding to residues 581 to 589, inclusive, with reference to SEQ ID NO: 313, has a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 321. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 1 amino acid substitution relative to SEQ ID NO: 321. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 2 amino acid substitutions relative to SEQ ID NO: 321. In particular embodiments, the 581-589 region of the engineered VP capsid polypeptide has a sequence that is identical to SEQ ID NO: 321. [0409] In some embodiments, the 581-589 region of the engineered VP capsid polypeptide, corresponding to residues 581 to 589, inclusive, with reference to SEQ ID NO: 313, has a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 322. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 1 amino acid substitution relative to SEQ ID NO: 322. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 2 amino acid substitutions relative to SEQ ID NO: 322. In particular embodiments, the 581-589 region of the engineered VP capsid polypeptide has a sequence that is identical to SEQ ID NO: 322. [0410] In some embodiments, the 581-589 region of the engineered VP capsid polypeptide, corresponding to residues 581 to 589, inclusive, with reference to SEQ ID NO: 313, has a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 323. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 1 amino acid substitution relative to SEQ ID NO: 323. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 2 amino acid substitutions relative to SEQ ID NO: 323. In particular embodiments, the 581-589 region of the engineered VP capsid polypeptide has a sequence that is identical to SEQ ID NO: 323. -174- ^{Docket No. 421688-718021 (718WO1)} [0411] In some embodiments, the 581-589 region of the engineered VP capsid polypeptide, corresponding to residues 581 to 589, inclusive, with reference to SEQ ID NO: 313, has a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 334. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 1 amino acid substitution relative to SEQ ID NO: 334. In some embodiments, the 581-589 region of the engineered VP capsid polypeptide comprises 2 amino acid substitutions relative to SEQ ID NO: 334. In particular embodiments, the 581-589 region of the engineered VP capsid polypeptide has a sequence that is identical to SEQ ID NO: 334. [0412] In some embodiments, the engineered AAV VP capsid polypeptide comprises a polypeptide sequence represented by the formula: (A)-(X)-(B) wherein: (A) is the polypeptide sequence of SEQ ID NO: 318 (MSAGGGGPLGDNNQGADGVGNASGDWHCDSTWMGDRVVTKSTRTWVLPSYNNHQ YREIKSGSVDGSNANAYFGYSTPWGYFDFNRFHSHWSPRDWQRLINNYWGFRPRSLRV KIFNIQVKEVTVQDSTTTIANNLTSTVQVFTDDDYQLPYVVGNGTEGCLPAFPPQVFTLP QYGYATLNRDNTENPTERSSFFCLEYFPSKMLRTGNNFEFTYNFEEVPFHSSFAPSQNLFK LANPLVDQYLYRFVSTNNTGGVQFNKNLAGRYANTYKNWFPGPMGRTQGWNLGSGV NRASVSAFATTNRMELEGASYQVPPQPNGMTNNLQGSNTYALENTMIFNSQPANPGTTA TYLEGNMLITSESETQPVNRVAYNVGGQMATNNQSSTTAP, corresponding to residues 193 to 580 of VP1 (SEQ ID NO: 313), residues 57 to 444 of VP2 (SEQ ID NO: 314), or residues 1 to 388 of VP3 (SEQ ID NO: 315)); (X) is the 581-589 region having a polypeptide sequence of any one of SEQ ID NO: 320 – SEQ ID NO: 349; and (B) is the polypeptide sequence of SEQ ID NO: 319 (IVPGSVWMERDVYLQGPIWAKIPETGAHFHPSPAMGGFGLKHPPPMMLIKNTPVPGNIT SFSDVPVSSFITQYSTGQVTVEMEWELKKENSKRWNPEIQYTNNYNDPQFVDFAPDSTG EYRTTRPIGTRYLTRPL, corresponding to residues 590 to 724 of VP1 (SEQ ID NO: 313), residues 454 to 588 of VP2 (SEQ ID NO: 314), or residues 398 to 532 of VP3 (SEQ ID NO: 315)). [0413] In some embodiments, the engineered AAV VP capsid polypeptide comprises a polypeptide sequence represented by the formula: (A)-(X)-(B) wherein: (A) is the polypeptide sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 318; (X) is the 581-589 region having a polypeptide sequence selected from the list of polypeptides -175- ^{Docket No. 421688-718021 (718WO1)} of any one of SEQ ID NO: 320 – SEQ ID NO: 349; and (B) is the polypeptide sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99%, or 100% sequence identity to SEQ ID NO: 319. [0414] In some examples, methods of producing delivery vectors herein comprising packaging a polynucleotide of the present disclosure in an AAV vector (e.g., a recombinant AAV5 comprising an engineered AAV5 VP capsid polypeptide). In some examples, methods of producing the delivery vectors described herein comprise, (a) introducing into a cell: (i) a polynucleotide disclosed herein; and (ii) a viral genome comprising a Replication (Rep) gene and Capsid (Cap) gene that encodes a wild-type AAV capsid protein or modified version thereof; (b) expressing in the cell the wild-type AAV capsid protein or modified version thereof; (c) assembling an AAV particle; and (d) packaging the polynucleotide disclosed herein in the AAV particle, thereby generating an AAV delivery vector. In some examples, any polynucleotide disclosed herein may be packaged in the AAV vector. In some examples, the recombinant vectors comprise one or more inverted terminal repeats and the inverted terminal repeats comprise a 5’ inverted terminal repeat, a 3’ inverted terminal repeat, and a mutated inverted terminal repeat. In some examples, the mutated terminal repeat lacks a terminal resolution site, thereby enabling formation of a self-complementary AAV. [0415] In some examples, a hybrid AAV vector may be produced by transcapsidation, e.g., packaging an inverted terminal repeat (ITR) from a first serotype into a capsid of a second serotype, wherein the first and second serotypes may be not the same. In some examples, the Rep gene and ITR from a first AAV serotype (e.g., AAV2) may be used in a capsid from a second AAV serotype (e.g., AAV5 or AAV9), wherein the first and second AAV serotypes may not be the same. As a non-limiting example, a hybrid AAV serotype comprising the AAV2 ITRs and AAV9 capsid protein may be indicated AAV2/9. In some examples, the hybrid AAV delivery vector comprises an AAV2/1, AAV2/2, AAV 2/4, AAV2/5, AAV2/8, or AAV2/9 vector. [0416] In some examples, the AAV vector may be a chimeric AAV vector. In some examples, the chimeric AAV vector comprises an exogenous amino acid or an amino acid substitution, or capsid proteins from two or more serotypes. In some examples, a chimeric AAV vector may be genetically engineered to increase transduction efficiency, selectivity, or a combination thereof. [0417] In some examples, the AAV vector comprises a self-complementary AAV genome. Self- complementary AAV genomes may be generally known in the art and contain both DNA strands which can anneal together to form double-stranded DNA. TABLE 9 shows exemplary sequences of plasmids comprising a recombinant polynucleotide, which can be used to produce an encapsidated recombinant polynucleotide by the methods described herein (e.g., transient -176- ^{Docket No. 421688-718021 (718WO1)} transfection to produce virus). A plasmid may encode a liver-enhancer as described herein. A plasmid may encode a liver-enhancer of SEQ ID NO: 362 or SEQ ID NO: 386. A plasmid may encode a liver-enhancer of SEQ ID NO: 362. A plasmid may further encode a core promoter as described herein paired with a liver-enhancer as described herein. A plasmid may encode a liver- enhancer of SEQ ID NO: 362 or SEQ ID NO: 386 paired with a core promoter of any one of SEQ ID NO: 81-236 or SEQ ID NO: 363-366. A plasmid may encode a liver-enhancer of SEQ ID NO: 362 paired with a core promoter of SEQ ID NO: 95. A plasmid may further encode a coding sequence of a polypeptide (e.g., a therapeutic polypeptide or protein). A plasmid may encode a liver-enhancer of SEQ ID NO: 362 paired with a core promoter of SEQ ID NO: 95 and sequence encoding therapeutic polypeptide for treating a liver disease. A plasmid may encode a CNS-enhancer of any one of SEQ ID NO: 1-80, SEQ ID NO: 360, SEQ ID NO: 385, or SEQ ID NO: 233-266. A plasmid may encode a CNS-enhancer of SEQ ID NO: 4. A plasmid may further encode a core promoter as described herein paired with a CNS-enhancer as described herein. A plasmid may encode a CNS-enhancer of any one of SEQ ID NO: 1-80, SEQ ID NO: 360, SEQ ID NO: 385, or SEQ ID NO: 233-266 paired with a core promoter of any one of SEQ ID NO: 81-236 or SEQ ID NO: 363-366. A plasmid may encode a CNS-enhancer of SEQ ID NO: 4 paired with a core promoter of SEQ ID NO: 95. A plasmid may further encode a coding sequence of a polypeptide (e.g., a therapeutic polypeptide or protein). A plasmid may encode a CNS-enhancer of SEQ ID NO: 4 paired with a core promoter of SEQ ID NO: 95 and sequence encoding therapeutic polypeptide for treating a CNS disease. A plasmid may encode a CNS- enhancer of SEQ ID NO: 4 paired with a core promoter of SEQ ID NO: 95 and sequence encoding progranulin. A plasmid may encode a CNS-enhancer of SEQ ID NO: 4 paired with a core promoter of SEQ ID NO: 95 and SEQ ID NO: 350. For example, a plasmid of SEQ ID NO: 355. The plasmid of SEQ ID NO: 355 encodes a recombinant polynucleotide of SEQ ID NO: 312 comprising a 5’ inverted terminal repeat of SEQ ID NO: 307, a 5’ stuffer sequence of SEQ ID NO: 309, a CNS-enhancer of SEQ ID NO: 4, a minP variant core promoter of SEQ ID NO: 95, a 5’ untranslated region of SEQ ID NO: 310 (which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a progranulin coding sequence (“GRN Coding Sequence”) of SEQ ID NO: 350, a WPRE3 post-transcriptional regulatory element of SEQ ID NO: 288, a polyadenylation signal of SEQ ID NO: 299, a transcriptional pause site of SEQ ID NO: 311, and a 3’ inverted terminal repeat of SEQ ID NO: 308, wherein the recombinant polynucleotide comprises two flanking ITRs. -177- ^{Docket No. 421688-718021 (718WO1)} TABLE 9 – Exemplary Plasmid Sequences Plasmid SEQ ID NO: Sequence MinP GRN SEQ ID NO: TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGC WPRE3 355 TCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGC AGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGGTGTCG GGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGT GCACCATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAA AATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTT GGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGG CGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCA GGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTC TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGCC CGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTC AGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCA CTAGGGGTTCCTGGATCCCTCGAGACGCGTCAATTGCCTAGGAGC TCCCCAAACCCTTCTCGGCTGCTGTGATGGGATAATTAGATGCGA GAGCTCAGCACAGATGATGCTCCAGTTGCTTAGCAACTAATGGTT TCCATGGAGACCGCAAAGCACAGCCTCCAGAGCAGCCAGTGAGC AGCTCGGCAGGGCAGGGAGAAGACGCAACTCCCTAGAGGGTATA TAAAGGAAGCTCGACTTCCAGCTTGGCATTCCGGGCTAGCGCCGC CACCATGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCT GGTGGCTGGAACGCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGC CTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTGCCGTCC CCTTCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTG GCCCCTGCCAGGTTGATGCCCACTGCTCTGCCGGCCACTCCTGCA TCTTTACCGTCTCAGGGACTTCCAGTTGCTGCCCCTTCCCAGAGGC CGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCA CTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAACA ACTCCGTGGGTGCCATCCAGTGCCCTGATAGTCAGTTCGAATGCC CGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGGGGT GCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACT GCTGTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCA TCACACCCACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCC AGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTC CGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGC TGCCCAGTGGGAAGTATGGCTGCTGCCCAATGCCCAACGCCACCT GCTGCTCCGATCACCTGCACTGCTGCCCCCAAGACACTGTGTGTG ACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGCTACCACG GACCTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAA ATGTGACATGGAGGTGAGCTGCCCAGATGGCTATACCTGCTGCCG TCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCCAGGCTGT GTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTG TGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGC CCTGGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCA CAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGT CCCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGC TGCTGTCCAATCCCAGAGGCTGTCTGCTGCTCGGACCACCAGCAC TGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGGGCAGTGTCAG CGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCCCG CCGGGCTTCCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCA CACCAGCTGCCCGGTGGGGCAGACCTGCTGCCCGAGCCTGGGTG GGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGAGG ATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGG CTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGCCACCT TCCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAGTGTG GGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGAC AACCGACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGT TGTGCTGATCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCA GCCAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGA CGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGAAAGCT TATCGAATTCCGCTCGAGATAATCAACCTCTGGATTACAAAATTT -178- ^{Docket No. 421688-718021 (718WO1)} Plasmid SEQ ID NO: Sequence GTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCT ATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCC CGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTAGTTC TTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGA CAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTTATTT GTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATCTATCTAGA AATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTT GTGTCTCTCAGCGGCCGCAATAAAATATCTTTATTTTCATTACATC TGTGTGTTGGTTTTTTGTGTGAATCGATAGTACTAACATACGCTCT CCATCAAAACAAAACGAAACAAAACAAACTAGCAAAATAGGCTG TCCCCAGTGCAAGTGCAGGTGCCAGAACATTTCTCTGTCGACCTG CAGAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCG CTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGG GCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAG AGAGGGAGTGGCCAAAAGCTTGGCGTAATCATGGTCATAGCTGT TTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATAC GAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTG AGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGT CGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGC GCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCG CTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTA TCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGG GGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAG GCCAGGAACCGTAAAAATCATGACCAAAATCCCTTAACGTGAGT TTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGAT CTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAAC AAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAG AGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGC AGATACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGGCCACC ACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAA TCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTA CCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGG TCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCG AACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAG AAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCG GTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCC AGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCA CCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCG GAGCCTATGGAAAAACGCCAGCAACGCGGCCGATTATCAAAAAG GATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATC AATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATG CTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCA TCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGG GAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGTGAG CCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCC GGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCC ATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCG CCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATC GTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTT CCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAA AAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGT TGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATT CTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGA GTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAG TTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAG CAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCG AAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTA ACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACC AGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAA AAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCT TCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCAT -179- ^{Docket No. 421688-718021 (718WO1)} Plasmid SEQ ID NO: Sequence GAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAG GGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTCTAAG AAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCA CGAGGCCCTTTCGTC [0418] In some embodiments, a plasmid for expressing progranulin comprises a sequence of SEQ ID NO: 355. SEQ ID NO: 355 comprises a recombinant polynucleotide of SEQ ID NO: 312. SEQ ID NO: 312 comprises a recombinant polynucleotide comprising a 5’ inverted terminal repeat of SEQ ID NO: 307, a 5’ stuffer sequence of SEQ ID NO: 309, a CNS-enhancer of SEQ ID NO: 4, a minP variant core promoter of SEQ ID NO: 95, a 5’ untranslated region of SEQ ID NO: 310 (which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a progranulin coding sequence of SEQ ID NO: 350 (comprising a sequence of SEQ ID NO: 358 encoding a progranulin signal peptide and a sequence of SEQ ID NO: 359), a HindIII restriction site, a WPRE3 post-transcriptional regulatory element of SEQ ID NO: 288, a XbalI restriction site, a polyadenylation signal of SEQ ID NO: 299, a NotI restriction site, a transcriptional pause site of SEQ ID NO: 311, a SalI restriction site, a PstI restriction site, and a 3’ inverted terminal repeat of SEQ ID NO: 308. In some embodiments, the plasmid comprising the recombinant polynucleotide has at least 80% sequence identity to SEQ ID NO: 355. In some embodiments, the plasmid comprising the recombinant polynucleotide has at least 85% sequence identity to SEQ ID NO: 355. In some embodiments, the plasmid comprising the recombinant polynucleotide has at least 90% sequence identity to SEQ ID NO: 355. In some embodiments, the plasmid comprising the recombinant polynucleotide has at least 95% sequence identity to SEQ ID NO: 355. In some embodiments, the plasmid comprising the recombinant polynucleotide has at least 96% sequence identity to SEQ ID NO: 355. In some embodiments, the plasmid comprising the recombinant polynucleotide has at least 97% sequence identity to SEQ ID NO: 355. In some embodiments, the plasmid comprising the recombinant polynucleotide has at least 98% sequence identity to SEQ ID NO: 355. In some embodiments, the plasmid comprising the recombinant polynucleotide has at least 99% sequence identity to SEQ ID NO: 355. In some embodiments, the plasmid comprising the recombinant polynucleotide comprises 100% sequence identity to SEQ ID NO: 355. In some embodiments, the plasmid comprising the recombinant polynucleotide is SEQ ID NO: 355. In some embodiments, the recombinant polynucleotide has at least 60%, 65%, 70% 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence comprising the recombinant polynucleotide between the ITRs of SEQ ID NO: 355. -180- ^{Docket No. 421688-718021 (718WO1)} [0419] In some examples, the delivery vector may be a retroviral vector. In some examples, the retroviral vector may be a Moloney Murine Leukemia Virus vector, a spleen necrosis virus vector, or a vector derived from the Rous Sarcoma Virus, Harvey Sarcoma Virus, avian leukosis virus, human immunodeficiency virus, myeloproliferative sarcoma virus, or mammary tumor virus, or a combination thereof. In some examples, the retroviral vector may be transfected such that the majority of sequences coding for the structural genes of the virus (e.g., gag, pol, and env) may be deleted and replaced by the gene(s) of interest. [0420] In some examples, the delivery vehicle may be a non-viral vector. In some examples, the delivery vehicle may be a plasmid. In some embodiments, the plasmid may be pGL4. In some embodiments, the plasmid comprises DNA. In some embodiments, the plasmid comprises RNA. In some examples, the plasmid comprises circular double-stranded DNA. In some examples, the plasmid may be linear. In some examples, the plasmid comprises one or more genes of interest and one or more regulatory elements. In some examples, the plasmid comprises a bacterial backbone containing an origin of replication and an antibiotic resistance gene or other selectable marker for plasmid amplification in bacteria. In some examples, the plasmid may be a minicircle plasmid. In some examples, the plasmid contains one or more genes that provide a selective marker to induce a target cell to retain the plasmid. In some examples, the plasmid may be formulated for delivery through injection by a needle carrying syringe. In some examples, the plasmid may be formulated for delivery via electroporation. In some examples, the plasmids may be engineered through synthetic or other suitable means known in the art. For example, in some cases, the genetic elements may be assembled by restriction digest of the desired genetic sequence from a donor plasmid or organism to produce ends of the DNA which may then be readily ligated to another genetic sequence. Methods of Regulating Payload Translation [0421] In some embodiments, the present disclosure provides a method of inserting a polynucleotide comprising the promoter as described herein and the payload into a recombinant polynucleotide cassette. The recombinant polynucleotide cassette may further modulate expression of the payload (e.g., by modulating translation). In some embodiments, the recombinant polynucleotide cassette modulates stability of the payload RNA. In some embodiments, the recombinant polynucleotide cassette comprises a 5’UTR effector region. In some embodiments, the recombinant polynucleotide cassette comprises a 3’UTR effector region. In some embodiments, the payload is codon optimized in the recombinant polynucleotide cassette. In some embodiments, an intron is inserted into the 5’UTR effector region or the -181- ^{Docket No. 421688-718021 (718WO1)} sequence of the payload. In some embodiments, the intron is a natural intron or a synthetic intron. [0422] In some embodiments, the recombinant polynucleotide cassette comprises the promoter as described herein, the payload, and one or more of: a 5’UTR effector region; a 3’UTR effector region; a codon optimized sequence of the payload; and an intron in the sequence of the payload. In some embodiments, translation of the payload increases from the recombinant polynucleotide cassette comprising one or more of the 5’UTR effector region, the 3’UTR effector region, a codon optimized sequence of the payload, and the intron in the sequence of the payload compared to from a recombinant polynucleotide cassette lacking the one or more of the 5’UTR effector region, the 3’UTR effector region, a codon optimized sequence of the payload, and the intron in the sequence of the payload. In some embodiments, translation of the payload decreases from the recombinant polynucleotide cassette comprising one or more of the 5’UTR effector region, the 3’UTR effector region, a codon optimized sequence of the payload, and the intron in the sequence of the payload compared to from a recombinant polynucleotide cassette lacking the one or more of the 5’UTR effector region, the 3’UTR effector region, a codon optimized sequence of the payload, and the intron in the sequence of the payload. [0423] In some embodiments, the 5’ UTR effector region comprises one or more of: a structural element; a sequence motif; a nucleotide base content comprising a G/C content of at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or 100%; and a 5’ UTR intron. In some embodiments, the structural element is a site that is in a conformation with the 5’cap so that the 5’cap is inaccessible or has low accessibility to the translation machinery (e.g., also referred to as “a cap-burying site”), resulting in decreased or no translation compared to a 5’UTR lacking this structural element. In some embodiments, the structural element is an Internal Ribosome Entry Site (IRES). In some embodiments, the structural element is an RNA pseudoknot. In some embodiments, the structural element is an Iron Responsive Element (IRE). In some embodiments, the structural element is a non-coding translation modulatory structure. In some embodiments, the structural element is a hairpin. In some embodiments, the structural element is a sequence (e.g., a cap-burying site sequence, an IRES, an RNA pseudoknot, an IRE, or a non-coding translation modulatory structure), that changes conformation when a sequence element contacts a target RNA with which it has at least partial complementarity, such that the rate of translation of the payload downstream of the structural element is increased or decreased compared to translation of the payload prior to the sequence element contacting the target RNA. In some embodiments, the 5’UTR effector region further comprises the sequence element, wherein a nucleic acid sequence of the sequence element is at least partially complementary to a -182- ^{Docket No. 421688-718021 (718WO1)} sequence of a target RNA and wherein conformation of the structural element changes when the sequence element contacts the target RNA with which it has at least partial complementarity. In some embodiments, the 5’ UTR intron is a natural intron, synthetic intron, or a fragment thereof. [0424] In some embodiments, the 3’ UTR comprises one or more of: a site that recruits polyA tail machinery; an miRNA binding site; or a sequence motif. In some embodiments, the poly(A) tail recruitment machinery comprises an enzyme. In some embodiments, the length of the poly(A) tail modulates protein expression from the polynucleotide. In some embodiments, the 3’UTR effector region comprises one, two, three, four, five, six, seven, eight, nine, ten, or more miRNA binding sites. In some embodiments, the miRNA binding sites are for the same miRNA. In some embodiments, the miRNA binding sites are for different miRNA. In some embodiments, the sequence motif is an AC-rich motif. In some embodiments, the sequence motif is an AU-rich element (ARE). [0425] In some embodiments, the codon optimized sequence of the therapeutic polynucleotide is a least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or 100% codon optimized. In some embodiments, the intron in the sequence of the therapeutic polynucleotide is a natural intron, synthetic intron, or a fragment thereof. In some embodiments, the recombinant polynucleotide cassette is encoded by a DNA vector. [0426] In some embodiments, the combination of the promoter and payload as described herein in the recombinant polynucleotide cassette results in the payload being expressed at a therapeutic level for reducing or alleviating at least one symptom of the disease or disorder. The therapeutic level can be -0.25-fold, -0.5-fold, 0-fold, 0.25-fold, 0.5-fold, 0.75-fold, 1-fold, 1.5- fold, 2-fold, or 4-fold greater than the biological level of the payload. Methods of Treatment and Pharmaceutical Compositions [0427] Methods for treatment of diseases or disorders characterized by aberrant gene expression are also encompassed by the present disclosure. Said methods include administering a therapeutically effective amount of a transgene as part of a recombinant polynucleotide cassette. The recombinant polynucleotide cassette of the disclosure can be formulated in pharmaceutical compositions. These compositions can comprise, in addition to one or more of the recombinant polynucleotide cassettes, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on the route of administration, e.g., oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes. -183- ^{Docket No. 421688-718021 (718WO1)} [0428] Pharmaceutical compositions for oral administration can be in tablet, capsule, powder, or liquid form. A tablet can include a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included. [0429] For intravenous, cutaneous, or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilizers, buffers, antioxidants and/or other additives can be included, as required. [0430] In some embodiments, the polynucleotide of the present disclosure or recombinant polynucleotide cassette of the present disclosure may be administered to cells via a lipid nanoparticle. In some embodiments, the lipid nanoparticle may be administered at the appropriate concentration according to standard methods appropriate for the target cells. [0431] In some embodiments, the polynucleotide of the present disclosure or recombinant polynucleotide cassette of the present disclosure may be administered to cells via a viral vector. In some embodiments, the viral vector may be administered at the appropriate multiplicity of infection according to standard transduction methods appropriate for the target cells. Titers of the virus vector or capsid to administer can vary depending on the target cell type and number and can be determined by those of skill in the art. In some embodiments, at least about 10² infections units are administered. In some embodiments, at least about 10³, 10⁴, 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², or 10¹³ infectious units are administered. [0432] In some embodiments, the polynucleotide or recombinant polynucleotide cassette is introduced to cells of any type, including, but not limited to neural cells, cells of the eye (including retinal cells, retinal pigment epithelium, and corneal cells), lung cells, epithelial cells, skeletal muscle cells, dendritic cells, hepatic cells, pancreatic cells, bone cells, hematopoietic stem cells, spleen cells, keratinocytes, fibroblasts, endothelial cells, prostate cells, and heart cells. [0433] In some embodiments, the polynucleotide or the disclosure or the recombinant polynucleotide cassette of the disclosure may be introduced to cells in vitro via a viral vector for administration of modified cells to a subject. In some embodiments, a viral vector encoding the -184- ^{Docket No. 421688-718021 (718WO1)} polynucleotide of the disclosure or the recombinant polynucleotide cassette of the disclosure is introduced to cells that have been removed from a subject. In some embodiments, the modified cells are placed back in the subject following introduction of the viral vector. [0434] In some embodiments, a dose of modified cells is administered to a subject according to the age and species of the subject, disease or disorder to be treated, as well as the cell type and mode of administration. In some embodiments, at least about 10² – 10⁸ cells are administered per dose. In some embodiments, cells transduced with viral vector are administered to a subject in an effective amount. [0435] In some embodiments, the dose of viral vector administered to a subject will vary according to the age of the subject, the disease or disorder to be treated, and mode of administration. In some embodiments, the dose for achieving a therapeutic effect is a virus titer of at least about 10², 10³, 10⁴, 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², 10¹³, 10¹⁴, 10¹⁵, 10¹⁶ or more transducing units. [0436] Administration of the pharmaceutically useful polynucleotide of the present disclosure or the polynucleotide cassette of the present disclosure is preferably in a “therapeutically effective amount” or “prophylactically effective amount” (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of protein aggregation disease being treated. Prescription of treatment, e.g., decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980. [0437] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated. [0438] A recombinant polynucleotide, plasmid, vector, and/or pharmaceutical composition of the present disclosure can be used in a method of treating a disorder in a subject in need thereof. A disorder can be a disease, a condition, a genotype, a phenotype, or any state associated with an adverse effect. In some embodiments, treating a disorder can comprise preventing, slowing progression of, reversing, or alleviating symptoms of the disorder. A method of treating a disorder can comprise delivering a recombinant polynucleotide as disclosed herein to a cell of a subject in need thereof and expressing the payload in the cell. A method of treating a disorder -185- ^{Docket No. 421688-718021 (718WO1)} can comprise delivering a recombinant polynucleotide as disclosed herein to a cell of a subject in need thereof and expressing the progranulin in the cell. In some embodiments, a recombinant polynucleotide of the present disclosure can be used to treat a genetic disorder (e.g., FTD). In some embodiments, a recombinant polynucleotide of the present disclosure can be used to treat a neurodegenerative disorder (e.g., FTD, ALS, Alzheimer’s Disease, Parkinson’s Disease, or dementia). In some embodiments, a recombinant polynucleotide of the present disclosure can be used to treat a condition associated with one or more mutations. [0439] In some embodiments, the recombinant polynucleotides of the present disclosure express the payload, which results in increased protein expression levels corresponding to the payload in the cell, tissue, or subject. For example, a recombinant polynucleotide encoding progranulin can increase progranulin expression levels in a cell, tissue, or subject. The recombinant polynucleotides of the present disclosure produce a from 1.1-fold to 1000-fold increased protein expression in the cell, tissue, or subject. The recombinant polynucleotides of the present disclosure produce a from 1.1-fold to 1000-fold, from 1.5-fold to 1000-fold, from 2-fold to 1000-fold, from 5-fold to 1000-fold, from 10-fold to 1000-fold, from 20-fold to 1000-fold, from 50-fold to 1000-fold, from 100-fold to 1000-fold, from 200-fold to 1000-fold, from 500-fold to 1000-fold, from 1.1-fold to 10-fold, from 1.5-fold to 10-fold, from 2-fold to 10-fold, from 5-fold to 10-fold, from 10-fold to 100-fold, from 20-fold to 100-fold, or from 50-fold to 100-fold increased protein expression in the cell, tissue, or subject. In some embodiments, the recombinant polynucleotides of the present disclosure produce at least 1.1-fold, at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 200-fold, or at least 500-fold increased protein expression in the cell, tissue, or subject. Increase in protein expression can be measured by an assay comparing a sample or subject treated with the recombinant polynucleotide to a control sample or subject not treated with the recombinant polynucleotide. [0440] In some embodiments, a protein encoded by a recombinant polynucleotide is expressed at different levels in a first cell type, tissue type, or organ than in a second cell type, tissue type, or organ. For example, progranulin encoded by a recombinant polynucleotide is expressed at a different level in a cerebrospinal fluid of a subject than in a serum of a subject. In some embodiments, a recombinant polynucleotide expresses a protein in a first cell type, tissue type, or organ at a level that is at least 0.001-fold, at least 0.005-fold, at least 0.01-fold, at least 0.02- fold, at least 0.05-fold, at least 0.1-fold, at least 0.2-fold, at least 0.25-fold, at least 0.5-fold, at least 1-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, at least 100-fold, at least 200-fold, at least 500- -186- ^{Docket No. 421688-718021 (718WO1)} fold, or at least 1000-fold an expression level of the protein in a second cell type, tissue type, or organ. [0441] In some embodiments, a protein encoded by a recombinant polynucleotide is expressed at different levels in a first cell type, tissue type, or organ than in a second cell type, tissue type, or organ. For example, progranulin encoded by a recombinant polynucleotide is expressed at a different level in a cerebrospinal fluid of a subject than in a serum of a subject. In some embodiments, a recombinant polynucleotide expresses progranulin in a first cell type, tissue type, or organ at a level that is at least 0.001-fold, at least 0.005-fold, at least 0.01-fold, at least 0.02-fold, at least 0.05-fold, at least 0.1-fold, at least 0.2-fold, at least 0.25-fold, at least 0.5-fold, at least 1-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, at least 100-fold, at least 200-fold, at least 500- fold, or at least 1000-fold higher than an expression level of the protein in a second cell type, tissue type, or organ. In some embodiments, a recombinant polynucleotide expresses progranulin in cerebral spinal fluid (CSF) at a level that is at least 0.001-fold, at least 0.005-fold, at least 0.01-fold, at least 0.02-fold, at least 0.05-fold, at least 0.1-fold, at least 0.2-fold, at least 0.25- fold, at least 0.5-fold, at least 1-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 15- fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold higher than an expression level of progranulin in serum. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is at least 0.001-fold, at least 0.005-fold, at least 0.01-fold, at least 0.02-fold, at least 0.05-fold, at least 0.1-fold, at least 0.2-fold, at least 0.25-fold, at least 0.5-fold, at least 1-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 20-fold to 500-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 20-fold to 200-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 20-fold to 100-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 20-fold to 50- fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 20-fold to 30-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 1-fold to 200-fold higher -187- ^{Docket No. 421688-718021 (718WO1)} than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 1-fold to 50-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 1-fold to 25-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 1-fold to 20-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 1-fold to 15-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 1-fold to 10-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 1-fold to 5-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 1-fold to 3-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 1-fold to 2-fold higher than an expression level of progranulin in CSF. In some embodiments, a recombinant polynucleotide expresses progranulin in serum at a level that is from 0.001-fold to 1-fold higher than an expression level of progranulin in CSF. [0442] In some embodiments, a recombinant polynucleotide expresses a protein in a first cell type, tissue type, or organ at a level that is not less than 0.001-fold and not more than 100-fold, not less than 0.01-fold and not more than 100-fold, not less than 0.05-fold and not more than 100-fold, not less than 0.1-fold and not more than 100-fold, not less than 0.2-fold and not more than 100-fold, not less than 0.25-fold and not more than 100-fold, not less than 0.5-fold and not more than 100-fold, not less than 1-fold and not more than 100-fold, not less than 5-fold and not less than 100-fold, not less than 10-fold and not more than 100-fold, not less than 0.001-fold and not more than 50-fold, not less than 0.01-fold and not more than 50-fold, not less than 0.05-fold and not more than 50-fold, not less than 0.1-fold and not more than 50-fold, not less than 0.2- fold and not more than 50-fold, not less than 0.25-fold and not more than 50-fold, not less than 0.5-fold and not more than 50-fold, not less than 1-fold and not more than 50-fold, not less than 5-fold and not more than 50-fold, not less than 10-fold and not more than 50-fold, not less than 0.001-fold and not more than 10-fold, not less than 0.01-fold and not more than 10-fold, not less than 0.05-fold and not more than 10-fold, not less than 0.1-fold and not more than 10-fold, not less than 0.2-fold and not more than 10-fold, not less than 0.25-fold and not more than 10-fold, not less than 0.5-fold and not more than 10-fold, not less than 1-fold and not more than 10-fold, -188- ^{Docket No. 421688-718021 (718WO1)} or not less than 5-fold and not more than 10-fold an expression level of the protein in a second cell type, tissue type, or organ. [0443] In some embodiments, a recombinant polynucleotide expresses progranulin in a first cell type, tissue type, or organ at a level that is not less than 0.001-fold and not more than 100-fold, not less than 0.01-fold and not more than 100-fold, not less than 0.05-fold and not more than 100-fold, not less than 0.1-fold and not more than 100-fold, not less than 0.2-fold and not more than 100-fold, not less than 0.25-fold and not more than 100-fold, not less than 0.5-fold and not more than 100-fold, not less than 1-fold and not more than 100-fold, not less than 5-fold and not more than 100-fold, not less than 10-fold and not more than 100-fold, not less than 0.001-fold and not more than 50-fold, not less than 0.01-fold and not more than 50-fold, not less than 0.05- fold and not more than 50-fold, not less than 0.1-fold and not more than 50-fold, not less than 0.2-fold and not more than 50-fold, not less than 0.25-fold and not more than 50-fold, not less than 0.5-fold and not more than 50-fold, not less than 1-fold and not more than 50-fold, not less than 5-fold and not more than 50-fold, not less than 10-fold and not more than 50-fold, not less than 0.001-fold and not more than 10-fold, not less than 0.01-fold and not more than 10-fold, not less than 0.05-fold and not more than 10-fold, not less than 0.1-fold and not more than 10-fold, not less than 0.2-fold and not more than 10-fold, not less than 0.25-fold and not more than 10- fold, not less than 0.5-fold and not more than 10-fold, not less than 1-fold and not more than 10- fold, or not less than 5-fold and not more than 10-fold higher than an expression level of progranulin in a second cell type, tissue type, or organ. A first cell type can be a blood cell. A first tissue type can be serum. A first organ can be a spleen or liver. A second cell type can be a neuronal cell type. A second tissue type can be a neuronal tissue. A second organ can be a central nervous system organ, e.g., brain or spinal cord. Diseases and Disorders [0444] In some embodiments, the recombinant polynucleotide of the disclosure or the recombinant polynucleotide cassette of the disclosure is used for treating a disease or disorder. In some embodiments, the disease or disorder is associated with abnormal expression of a gene or protein. In some embodiments, the disease or disorder is a CNS disease or disorder. In some embodiments the disease or disorder is AADC Deficiency, Parkinson’s Disease, Adrenomyeloneuropathy, Alzheimer’s Disease, Canavan Disease, Wilson’s disease, Amyotrophic Lateral Sclerosis (ALS), Batten Disease, CLN1 Disease, Huntington’s Disease, Down syndrome, Parkinson’s Disease, Freidreich’s Ataxia, Krabbe Disease, Gaucher disease type 2, Parkinson’s Disease with GBA1 mutations (PD-GBA), Neuronpathic Gaucher’s Disease, Synucleinopathies, Fabry Disease, GM1 Gangliosidosis, Frontotemporal dementia with GRN -189- ^{Docket No. 421688-718021 (718WO1)} mutations (FTD-GRN), Tay-Sachs Disease, Sandhoff Disease, Gm2 Gangliosidosis, Sanfilippo Disease type B, Epileptic Encephalopathy, Protocki-Lupski Syndrome, Danon Disease, Tauopathies, Corticobasal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Rett syndrome, MPS-IIIB, Ornithine Transcarbamylase Deficiency, Charcot-Marie-Tooth neuropathy, Sanfilippo disease type A, Spinal Muscular Atrophy, or Leigh Syndrome. [0445] In some embodiments, a polynucleotide of the present disclosure or the recombinant polynucleotide cassette of the present disclosure may be administered using a viral vector (e.g., an AAV vector) to a subject in need thereof. For example, the subject in need thereof may have or be at risk for frontotemporal dementia. Upon administration of said polynucleotide or said recombinant polynucleotide cassette, a payload may be expressed in a cell type or tissue type of interest (e.g., a neuronal cell or CNS tissue). The payload may be selectively transcribed in the cell type or tissue type of interest, thereby preventing unwanted adverse effects in the subject due to expression in non-target tissues. The subject can be a human or a non-human animal. Thus, the polynucleotides disclosed herein or the recombinant polynucleotide cassettes disclosed herein can serve as a therapeutically effective vector replacement therapy that senses endogenous nucleic acids to regulate expression of a transgene payload and prevent or minimize adverse side effects from overexpression of a transgene payload. [0446] In some embodiments, the recombinant polynucleotide of the disclosure or the recombinant polynucleotide cassette of the disclosure is used for treating a disease or disorder associated with abnormal expression of a gene or protein. In some embodiments the disease or disorder is a liver disease or liver disorder. In some embodiments, the disease or disorder is haemophilia A, haemophilia B, ornithine transcarbamylase deficiency, methylmalonic acidemia, or alpha-1 anti-trypsin deficiency. [0447] In some embodiments, a polynucleotide of the present disclosure or the recombinant polynucleotide cassette of the present disclosure may be administered using a viral vector (e.g., an AAV vector) to a subject in need thereof. For example, the subject in need thereof may have or be at risk for a liver disease or liver disorder. Upon administration of said polynucleotide or said recombinant polynucleotide cassette, a payload sequence may be expressed in a cell type or tissue type of interest (e.g., a hepatic cell or liver tissue). The payload sequence may be selectively transcribed in the cell type or tissue type of interest, thereby preventing unwanted adverse effects in the subject due to expression in non-target tissues. The subject can be a human or a non-human animal. Thus, the polynucleotides disclosed herein or the recombinant polynucleotide cassettes disclosed herein can serve as a therapeutically effective vector -190- ^{Docket No. 421688-718021 (718WO1)} replacement therapy that senses endogenous nucleic acids to regulate expression of a transgene payload and prevent or minimize adverse side effects from overexpression of a transgene payload. Treatment of Diseases associated with GRN and Therapeutic Applications Thereof [0001] An exemplary gene associated with a disease or condition that can be treated by a recombinant polynucleotide as described herein is GRN. A recombinant polynucleotide of the present disclosure encoding a GRN payload under transcriptional control of a promoter can have therapeutic applications. Therapeutic applications include treatment of a disease or disorder. Treatment of a disease or disorder can comprise preventing, alleviating a symptom of, reversing progression of, or reducing an underlying cause of the disease or condition. The recombinant polynucleotides described herein and below can facilitate the therapeutic use by allowing for payload expression at a high enough level for the payload to have a therapeutic effect. [0448] For example, treatment with a recombinant polynucleotide comprising a CNS enhancer of any one of SEQ ID NO: 1-80, SEQ ID NO: 360, or SEQ ID NO: 385 and a sequence encoding progranulin. In some embodiments, the treatment is with a recombinant polynucleotide comprising a CNS enhancer of SEQ ID NO: 4 and a sequence encoding progranulin. In some embodiments, the treatment is with a recombinant polynucleotide comprising a CNS enhancer of any one of SEQ ID NO: 1-80, SEQ ID NO: 360, or SEQ ID NO: 385 paired with a core promoter of any one of SEQ ID NO: 81-236 or SEQ ID NO: 363-366 and a sequence encoding progranulin. In some embodiments, the treatment is with a recombinant polynucleotide comprising a CNS enhancer of SEQ ID NO: 4 paired with a core promoter of SEQ ID NO: 95 and a sequence encoding progranulin. In some embodiments, the recombinant polynucleotide comprises a CNS-enhancer (e.g., SEQ ID NO: 4), a minP variant core promoter (e.g., SEQ ID NO: 95), a payload encoding a progranulin protein (e.g., encoding a protein of SEQ ID NO: 352), a post-transcriptional regulator element (e.g., a WPRE3 of SEQ ID NO: 288), a polyadenylation signal (e.g., SEQ ID NO: 299), and a transcriptional pause site (e.g., SEQ ID NO: 311). In some embodiments, the recombinant polynucleotide further comprises a 5’ stuffer sequence (e.g., SEQ ID NO: 309). In some embodiments, the recombinant polynucleotide comprises a 5’ untranslated region. The 5’ untranslated region may comprise a sequence that overlaps with the promoter (e.g., SEQ ID NO: 310 which includes the 3’ 7 nucleotides of a minP variant core promoter). The 5’ untranslated region can comprise a Kozak sequence (e.g., SEQ ID NO: 354) and can further comprise additional nucleotides 5’ of the Kozak sequence (e.g., comprising 7 nucleotides overlapping the 3’ end of the core promoter and comprising additional nucleotides between the 3’ end of the core promoter and the Kozak sequence). The 5’ untranslated region can comprise a sequence of SEQ ID NO: 353 and can further comprise a -191- ^{Docket No. 421688-718021 (718WO1)} region 5’ of SEQ ID NO: 353 that overlaps the core promoter (e.g., comprising 7 nucleotides overlapping the 3’ end of the core promoter). In some embodiments, the recombinant polynucleotide comprises a CNS-enhancer (e.g., SEQ ID NO: 4), a minP variant core promoter (e.g., SEQ ID NO: 95), a payload encoding a progranulin protein (e.g., encoding a protein of SEQ ID NO: 350), a WPRE3 (e.g., SEQ ID NO: 288), a polyadenylation signal (e.g., SEQ ID NO: 299), and a transcriptional pause site (e.g., SEQ ID NO: 311). In some embodiments, the recombinant polynucleotide comprises SEQ ID NO: 4, SEQ ID NO: 95, SEQ ID NO: 350, SEQ ID NO: 288, SEQ ID NO: 299, and SEQ ID NO: 311. In some embodiments, the recombinant polynucleotide further comprises SEQ ID NO: 309. In some embodiments, the recombinant polynucleotide comprises SEQ ID NO: 310 which includes the 3’ 7 nucleotides of a minP variant core promoter (e.g., SEQ ID NO: 95). In some embodiments, the recombinant polynucleotide comprises SEQ ID NO: 353. In some embodiments, the recombinant polynucleotide comprises SEQ ID NO: 4, SEQ ID NO: 95, SEQ ID NO: 353, SEQ ID NO: 350, SEQ ID NO: 288, SEQ ID NO: 299, and SEQ ID NO: 311. In some embodiments, a recombinant polynucleotide may comprise, from 5’ to 3’, a 5’ stuffer sequence of SEQ ID NO: 309, a CNS-enhancer of SEQ ID NO: 4, a minP variant core promoter of SEQ ID NO: 95, a 5’ untranslated region of SEQ ID NO: 310 (which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a progranulin coding sequence of SEQ ID NO: 350 (comprising a sequence of SEQ ID NO: 358 encoding a progranulin signal peptide and a sequence of SEQ ID NO: 359), a HindIII restriction site, a WPRE3 post-transcriptional regulatory element of SEQ ID NO: 288, a XbalI restriction site, a polyadenylation signal of SEQ ID NO: 299, a NotI restriction site, a transcriptional pause site of SEQ ID NO: 311, a SalI restriction site, and a PstI restriction site. For example, the recombinant polynucleotide comprises a sequence of SEQ ID NO: 312. In some embodiments, a recombinant polynucleotide (e.g., a recombinant polynucleotide of SEQ ID NO: 312, as shown in FIG.36) may comprise, from 5’ to 3’, a 5’ ITR (e.g., SEQ ID NO: 307), a 5’ stuffer sequence (e.g., SEQ ID NO: 309), a CNS-enhancer (e.g., SEQ ID NO: 4), a minP variant core promoter (e.g., SEQ ID NO: 95), a 5’ UTR (e.g., SEQ ID NO: 310 which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a coding sequence (e.g., SEQ ID NO: 350), a post-transcriptional regulatory element (e.g., SEQ ID NO: 288), a polyA signal (e.g., SEQ ID NO: 299), a transcriptional pause site (e.g., SEQ ID NO: 311), and a 3’ ITR (e.g., SEQ ID NO: 308). In some embodiments, a recombinant polynucleotide may comprise, from 5’ to 3’, SEQ ID NO: 307, SEQ ID NO: 309, SEQ ID NO: 4, SEQ ID NO: 95, SEQ ID NO: 310 which comprises 7 nucleotides of the 3’ end of the core promoter of SEQ ID NO: 95 and a Kozak sequence of SEQ ID NO: 354, SEQ ID -192- ^{Docket No. 421688-718021 (718WO1)} NO: 350, a post-transcriptional regulatory element (e.g., SEQ ID NO: 288), a polyA signal (e.g., SEQ ID NO: 299, SEQ ID NO: 311, and SEQ ID NO: 308. In some embodiments, a recombinant polynucleotide may comprise, from 5’ to 3’, SEQ ID NO: 307, SEQ ID NO: 309, SEQ ID NO: 4, SEQ ID NO: 95, SEQ ID NO: 353, SEQ ID NO: 350, SEQ ID NO: 288, SEQ ID NO: 299, SEQ ID NO: 311, and SEQ ID NO: 308. In some embodiments, a recombinant polynucleotide may comprise a 5’ stuffer sequence of SEQ ID NO: 309, a CNS-enhancer of SEQ ID NO: 4, a minP variant core promoter of SEQ ID NO: 95, a 5’ untranslated region of SEQ ID NO: 310 (which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a progranulin coding sequence of SEQ ID NO: 350 (comprising a sequence of SEQ ID NO: 358 encoding a progranulin signal peptide and a sequence of SEQ ID NO: 359), a HindIII restriction site, a WPRE3 post-transcriptional regulatory element of SEQ ID NO: 288, a XbalI restriction site, a polyadenylation signal of SEQ ID NO: 299, a NotI restriction site, a transcriptional pause site of SEQ ID NO: 311, a SalI restriction site, and a PstI restriction site. In some embodiments, a recombinant polynucleotide may comprise a 5’ inverted terminal repeat of SEQ ID NO: 307, a 5’ stuffer sequence of SEQ ID NO: 309, a CNS-enhancer of SEQ ID NO: 4, a minP variant core promoter of SEQ ID NO: 95, a 5’ untranslated region of SEQ ID NO: 310 (which overlaps with the core promoter and comprises 7 nucleotides of the 3’ end of the core promoter and a Kozak sequence of SEQ ID NO: 354), a progranulin coding sequence of SEQ ID NO: 350 (comprising a sequence of SEQ ID NO: 358 encoding a progranulin signal peptide and a sequence of SEQ ID NO: 359), a HindIII restriction site, a WPRE3 post-transcriptional regulatory element of SEQ ID NO: 288, a XbalI restriction site, a polyadenylation signal of SEQ ID NO: 299, a NotI restriction site, a transcriptional pause site of SEQ ID NO: 311, a SalI restriction site, a PstI restriction site, and a 3’ inverted terminal repeat of SEQ ID NO: 308. The recombinant polynucleotide may comprise at least 80% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 85% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 90% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 95% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 96% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 97% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 98% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least 99% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 100% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise a sequence of SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 80% sequence identity to -193- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 85% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 90% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 95% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 96% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 97% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 98% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise at least about 99% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 100% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise a sequence of SEQ ID NO: 312. The recombinant polynucleotide may comprise about 80% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 85% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 90% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 95% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 96% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 97% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 98% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 99% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise about 100% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 80% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 85% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 90% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 95% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 96% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 97% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 98% sequence identity to SEQ ID NO: 312. The recombinant polynucleotide may comprise 99% sequence identity to SEQ ID NO: 312. [0449] An exemplary disease or condition associated with GRN is frontotemporal dementia (FTD). Additional diseases or conditions associated with GRN that can be treated using a recombinant polynucleotide of the present disclosure include amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease, Parkinson’s Disease, stroke, Gaucher disease, arthritis, limbic- predominant age-related transactivation response DNA-binding protein 43 (TDP-43) encephalopathy, autism, neuronal ceroid lipofuscinosis (e.g., type 11 (CLN11)), dementia, and neurodegeneration, such as neurodegeneration associated with normal brain aging. -194- ^{Docket No. 421688-718021 (718WO1)} [0450] Progranulin, encoded by GRN, is a precursor protein cleaved to form granulin. GRN is expressed in peripheral and central nervous system tissues and is upregulated in microglia following injury. Both granulin and progranulin are implicated in a wide variety of functions, including development, inflammation, cell proliferation. and protein homeostasis. Mutations in GRN are implicated in frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease, Parkinson’s Disease, stroke, Gaucher disease, arthritis, limbic- predominant age-related transactivation response DNA-binding protein 43 (TDP-43) encephalopathy, autism, neuronal ceroid lipofuscinosis (e.g., type 11 (CLN11)), dementia, and neurodegeneration. Additionally, GRN has been shown to be anti-inflammatory. Therefore, GRN can potentially aid disease treatment as anti-inflammatory, such as for treating frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease, Parkinson’s Disease, stroke, Gaucher disease, arthritis, limbic-predominant age-related transactivation response DNA-binding protein 43 (TDP-43) encephalopathy, autism, neuronal ceroid lipofuscinosis (e.g., type 11 (CLN11)), dementia, and neurodegeneration. Furthermore, GRN can potentially aid disease treatment as anti-inflammatory for patients with normal GRN, such as for treating neurodegeneration caused by normal aging. Described herein are methods of increasing expression of GRN using recombinant polynucleotide expressing progranulin to treat a disease (e.g., amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease, Parkinson’s Disease, stroke, Gaucher disease, arthritis, limbic-predominant age-related transactivation response DNA- binding protein 43 (TDP-43) encephalopathy, autism, neuronal ceroid lipofuscinosis (e.g., type 11 (CLN11)), dementia, and neurodegeneration, such as neurodegeneration associated with normal brain aging). [0451] Mutations in GRN can lead to frontotemporal dementia (FTD), a neurodegenerative disease. Loss of function mutations leading to GRN haploinsufficiency can be implicated in familial and sporadic cases of frontotemporal dementia. GRN has anti-inflammatory properties, so expression of GRN can reduce inflammation, protecting against neurodegeneration. In FTD cases, decreased levels of progranulin are observed in the serum and cerebrospinal fluid of subjects with loss of function mutations and subjects without said mutations. Thus, the recombinant polynucleotides of the present disclosure can increase expression of progranulin as a means to restore or enhance progranulin levels. ALS, Alzheimer’s Disease, Parkinson’s Disease, and dementia also associated with loss of function GRN mutations. Thus, increasing expression of GRN can be used to treat LS, Alzheimer’s Disease, Parkinson’s Disease, and dementia. -195- ^{Docket No. 421688-718021 (718WO1)} [0452] In some embodiments, the recombinant polynucleotides as described above that expresses progranulin as the payload results in increased progranulin expression levels in the cell, tissue, or subject. The recombinant polynucleotides as described above that express progranulin as the payload produce a from 1.1-fold to 1000-fold increased progranulin expression in the cell, tissue, or subject. The recombinant polynucleotides of the present disclosure produce a from 1.1-fold to 1000-fold, from 1.5-fold to 1000-fold, from 2-fold to 1000-fold, from 5-fold to 1000-fold, from 10-fold to 1000-fold, from 20-fold to 1000-fold, from 50-fold to 1000-fold, from 100-fold to 1000-fold, from 200-fold to 1000-fold, from 500-fold to 1000-fold, from 1.1-fold to 10-fold, from 1.5-fold to 10-fold, from 2-fold to 10-fold, from 5-fold to 10-fold, from 10-fold to 100-fold, from 20-fold to 100-fold, or from 50-fold to 100-fold increased progranulin expression in the cell, tissue, or subject. In some embodiments, the recombinant polynucleotides as described above that express progranulin as the payload produce at least 1.1-fold, at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 200-fold, or at least 500-fold increased progranulin expression in the cell, tissue, or subject. Increase in progranulin expression can be measured by an assay comparing a sample or subject treated with the recombinant polynucleotide to a control sample or subject not treated with the recombinant polynucleotide. [0453] In some embodiments, a recombinant polynucleotide as described above that expresses progranulin as the payload expresses progranulin in cerebrospinal fluid at a level that is at least 0.001-fold, at least 0.005-fold, at least 0.01-fold, at least 0.02-fold, at least 0.05-fold, at least 0.1-fold, at least 0.2-fold, at least 0.25-fold, at least 0.5-fold, at least 1-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold an expression level of progranulin in serum. [0454] In some embodiments, a recombinant polynucleotide as described above that expresses progranulin as the payload expresses progranulin in serum at a level that is no more than 0.001- fold, no more than 0.005-fold, no more than 0.01-fold, no more than 0.02-fold, no more than 0.05-fold, no more than 0.1-fold, no more than 0.2-fold, no more than 0.25-fold, no more than 0.5-fold, no more than 1-fold, no more than 2-fold, no more than 5-fold, no more than 10-fold, no more than 15-fold, no more than 20-fold, no more than 25-fold, no more than 50-fold, no more than 75-fold, no more than 100-fold, no more than 200-fold, no more than 500-fold, or no more than 1000-fold an expression level of progranulin in cerebrospinal fluid. [0455] In some embodiments, a recombinant polynucleotide as described above that expresses progranulin as the payload expresses progranulin in cerebrospinal fluid at a level that is not less -196- ^{Docket No. 421688-718021 (718WO1)} than 0.001-fold and not more than 100-fold, not less than 0.01-fold and not more than 100-fold, not less than 0.05-fold and not more than 100-fold, not less than 0.1-fold and not more than 100- fold, not less than 0.2-fold and not more than 100-fold, not less than 0.25-fold and not more than 100-fold, not less than 0.5-fold and not more than 100-fold, not less than 1-fold and not more than 100-fold, not less than 5-fold and not more than 100-fold, not less than 10-fold and not more than 100-fold, not less than 0.001-fold and not more than 50-fold, not less than 0.01-fold and not more than 50-fold, not less than 0.05-fold and not more than 50-fold, not less than 0.1- fold and not more than 50-fold, not less than 0.2-fold and not more than 50-fold, not less than 0.25-fold and not more than 50-fold, not less than 0.5-fold and not more than 50-fold, not less than 1-fold and not more than 50-fold, not less than 5-fold and not more than 50-fold, not less than 10-fold and not more than 50-fold, not less than 0.001-fold and not more than 10-fold, not less than 0.01-fold and not more than 10-fold, not less than 0.05-fold and not more than 10-fold, not less than 0.1-fold and not more than 10-fold, not less than 0.2-fold and not more than 10- fold, not less than 0.25-fold and not more than 10-fold, not less than 0.5-fold and not more than 10-fold, not less than 1-fold and not more than 10-fold, or not less than 5-fold and not more than 10-fold an expression level of progranulin in serum. [0456] In some embodiments, a recombinant polynucleotide as described above that expresses progranulin as the payload expresses progranulin in serum at a level that is not less than 0.001- fold and not more than 100-fold, not less than 0.01-fold and not more than 100-fold, not less than 0.05-fold and not more than 100-fold, not less than 0.1-fold and not more than 100-fold, not less than 0.2-fold and not more than 100-fold, not less than 0.25-fold and not more than 100- fold, not less than 0.5-fold and not more than 100-fold, not less than 1-fold and not more than 100-fold, not less than 5-fold and not more than 100-fold, not less than 10-fold and not more than 100-fold, not less than 0.001-fold and not more than 50-fold, not less than 0.01-fold and not more than 50-fold, not less than 0.05-fold and not more than 50-fold, not less than 0.1-fold and not more than 50-fold, not less than 0.2-fold and not more than 50-fold, not less than 0.25-fold and not more than 50-fold, not less than 0.5-fold and not more than 50-fold, not less than 1-fold and not more than 50-fold, not less than 5-fold and not more than 50-fold, not less than 10-fold and not more than 50-fold, not less than 0.001-fold and not more than 10-fold, not less than 0.01-fold and not more than 10-fold, not less than 0.05-fold and not more than 10-fold, not less than 0.1-fold and not more than 10-fold, not less than 0.2-fold and not more than 10-fold, not less than 0.25-fold and not more than 10-fold, not less than 0.5-fold and not more than 10-fold, not less than 1-fold and not more than 10-fold, or not less than 5-fold and not more than 10-fold higher than an expression level of progranulin in the cerebrospinal fluid. -197- ^{Docket No. 421688-718021 (718WO1)} [0457] For example, a recombinant polynucleotide as described above that expresses progranulin as the payload under transcriptional control of a CNS enhancer paired with a core promoter as described herein express a peptide encoded by a payload sequence. In some embodiments, the payload sequence is a GRN sequence that is used to treat FTD. Treatment of FTD can comprise expressing progranulin in a subject. In some embodiments, treatment of FTD comprises expressing progranulin in a fluid (e.g., a cerebrospinal fluid) of a subject. The fluid can be secreted by a cell or tissue expressing the progranulin. The progranulin can be expressed in the cerebrospinal fluid at a level high enough to have a therapeutic effect. In some embodiments, the progranulin level high enough to have a therapeutic effect is at least 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 4 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 2 ng/mL to 4.5 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 10 ng/mL. In some embodiments, a progranulin level in a serum of the subject is not more than 300 ng/mL. [0458] In some embodiments, a recombinant polynucleotide as described above that expresses progranulin can be used to treat Amyotrophic Lateral Sclerosis (ALS). Treatment of ALS can comprise expressing progranulin in a subject. In some embodiments, treatment of ALS comprises expressing progranulin in a cerebrospinal fluid of a subject. The progranulin can be expressed in the cerebrospinal fluid at a level high enough to have a therapeutic effect. In some embodiments, the progranulin level high enough to have a therapeutic effect is at least 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 2 ng/mL to 4.5 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 10 ng/mL. In some embodiments, a progranulin level in a serum of the subject is not more than 300 ng/mL. [0459] In some embodiments, a recombinant polynucleotide as described above that expresses progranulin can be used to treat Alzheimer’s Disease. Treatment of Alzheimer’s Disease can comprise expressing progranulin in a subject. In some embodiments, treatment of Alzheimer’s Disease comprises expressing progranulin in a cerebrospinal fluid of a subject. The progranulin can be expressed in the cerebrospinal fluid at a level high enough to have a therapeutic effect. In some embodiments, the progranulin level high enough to have a therapeutic effect is at least 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 2 -198- ^{Docket No. 421688-718021 (718WO1)} ng/mL to 4.5 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 10 ng/mL. In some embodiments, a progranulin level in a serum of the subject is not more than 300 ng/mL. [0460] In some embodiments, a recombinant polynucleotide as described above that expresses progranulin can be used to treat Parkinson’s Disease. Treatment of Parkinson’s Disease can comprise expressing progranulin in a subject. In some embodiments, treatment of Parkinson’s Disease comprises expressing progranulin in a cerebrospinal fluid of a subject. The progranulin can be expressed in the cerebrospinal fluid at a level high enough to have a therapeutic effect. In some embodiments, the progranulin level high enough to have a therapeutic effect is at least 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 2 ng/mL to 4.5 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 10 ng/mL. In some embodiments, a progranulin level in a serum of the subject is not more than 300 ng/mL. [0461] In some embodiments, a recombinant polynucleotide as described above that expresses progranulin can be used to treat dementia. Treatment of dementia can comprise expressing progranulin in a subject. In some embodiments, treatment of dementia comprises expressing progranulin in a cerebrospinal fluid of a subject. The progranulin can be expressed in the cerebrospinal fluid at a level high enough to have a therapeutic effect. In some embodiments, the progranulin level high enough to have a therapeutic effect is at least 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 3 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 2 ng/mL to 4.5 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 10 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 100 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 10 ng/mL to 100 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 1 ng/mL to 30 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 10 ng/mL to 50 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 10 ng/mL to 30 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 70 ng/mL to 180 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is from 70 ng/mL to 300 ng/mL. In some embodiments, the progranulin level to have a therapeutic effect is comparable to a progranulin level of a healthy patient. In some embodiments, a progranulin level in a serum of the subject is not more than 300 ng/mL. -199- ^{Docket No. 421688-718021 (718WO1)} [0462] As used herein, the term “therapeutic polynucleotide” refers to a polynucleotide that is introduced into a cell and is capable of being expressed in the cell. [0463] As used herein, the term “polynucleotide” refers to a single or double-stranded polymer of deoxyribonucleotide (DNA) or ribonucleotide (RNA) bases read from the 5’ to the 3’ end. The term “RNA” is inclusive of dsRNA (double stranded RNA), snRNA (small nuclear RNA), lncRNA (long non-coding RNA), mRNA (messenger RNA), miRNA (microRNA) RNAi (inhibitory RNA), siRNA (small interfering RNA), shRNA (short hairpin RNA), tRNA (transfer RNA), rRNA (ribosomal RNA), snoRNA (small nucleolar RNA), and cRNA (complementary RNA). The term DNA is inclusive of cDNA, genomic DNA, and DNA-RNA hybrids. [0464] The term “ameliorating” refers to any therapeutically beneficial result in the treatment of a disease state, e.g., Rett syndrome, including prophylaxis, lessening in the severity or progression, remission, or cure thereof. [0465] The term “mammal” as used herein includes both humans and non-humans and include but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. [0466] Unless otherwise stated, whenever a range is recited, the range is inclusive of the recited endpoints. For example, the region from amino acid residue 581 to amino acid residue 589 of SEQ ID NO: 316 includes amino acid residues 581 and 589. [0467] The term percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refers to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN or other algorithms available to persons of skill) or by visual inspection. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared. [0468] For sequence comparison, typically one sequence acts as a reference sequence (also called the subject sequence) to which test sequences (also called query sequences) are compared. The percent sequence identity is defined as a test sequence’s percent identity to a reference sequence. For example, when stated “Sequence A having a sequence identity of 50% to Sequence B,” Sequence A is the test sequence and Sequence B is the reference sequence. When using a sequence comparison algorithm, test and reference sequences are input into a computer program, subsequence coordinates are designated, if necessary, and sequence algorithm program -200- ^{Docket No. 421688-718021 (718WO1)} parameters are designated. The sequence comparison algorithm then aligns the sequences to achieve the maximum alignment, based on the designated program parameters, introducing gaps in the alignment if necessary. The percent sequence identity for the test sequence(s) relative to the reference sequence can then be determined from the alignment of the test sequence to the reference sequence. The equation for percent sequence identity from the aligned sequence is as follows: [(Number of Identical Positions)/(Total Number of Positions in the Test Sequence)] × 100% [0469] For purposes herein, percent identity and sequence similarity calculations are performed using the BLAST algorithm for sequence alignment, which is described in Altschul et al., J. Mol. Biol.215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov/). The BLAST algorithm uses a test sequence (also called a query sequence) and a reference sequence (also called a subject sequence) to search against, or in some cases, a database of multiple reference sequences to search against. The BLAST algorithm performs sequence alignment by finding high-scoring alignment regions between the test and the reference sequences by scoring alignment of short regions of the test sequence (termed “words”) to the reference sequence. The scoring of each alignment is determined by the BLAST algorithm and takes factors into account, such as the number of aligned positions, as well as whether introduction of gaps between the test and the reference sequences would improve the alignment. The alignment scores for nucleic acids can be scored by set match/mismatch scores. For protein sequences, the alignment scores can be scored using a substitution matrix to evaluate the significance of the sequence alignment, for example, the similarity between aligned amino acids based on their evolutionary probability of substitution. For purposes herein, the substitution matrix used is the BLOSUM62 matrix. For purposes herein, the public default values of April 6, 2023 are used when using the BLASTN and BLASTP algorithms. The BLASTN and BLASTP algorithms then output a “Percent Identity” output value and a “Query Coverage” output value. The overall percent sequence identity as used herein can then be calculated from the BLASTN or BLASTP output values as follows: Percent Sequence Identity = (“Percent Identity” output value) × (“Query Coverage” output value) [0470] The following non-limiting examples illustrate the calculation of percent identity between two nucleic acids sequences. The percent identity is calculated as follows: [(number of identical nucleotide positions)/(total number of nucleotides in the test sequence)] × 100%. Percent identity is calculated to compare test sequence 1: AAAAAGGGGG (SEQ ID NO: 390) -201- ^{Docket No. 421688-718021 (718WO1)} (length = 10 nucleotides) to reference sequence 2: AAAAAAAAAA (SEQ ID NO: 391) (length = 10 nucleotides). The percent identity between test sequence 1 and reference sequence 2 would be [(5)/(10)] ×100% = 50%. Test sequence 1 has 50% sequence identity to reference sequence 2. In another example, percent identity is calculated to compare test sequence 3: CCCCCGGGGGGGGGGCCCCC (SEQ ID NO: 392) (length = 20 nucleotides) to reference sequence 4: GGGGGGGGGG (SEQ ID NO: 393) (length = 10 nucleotides). The percent identity between test sequence 3 and reference sequence 4 would be [(10)/(20)] ×100% = 50%. Test sequence 3 has 50% sequence identity to reference sequence 4. In another example, percent identity is calculated to compare test sequence 5: GGGGGGGGGG (SEQ ID NO: 393) (length = 10 nucleotides) to reference sequence 6: CCCCCGGGGGGGGGGCCCCC (SEQ ID NO: 392) (length = 20 nucleotides). The percent identity between test sequence 5 and reference sequence 6 would be [(10)/(10)] ×100% = 100%. Test sequence 5 has 100% sequence identity to reference sequence 6. [0471] The following non-limiting examples illustrate the calculation of percent identity between two protein sequences. The percent identity is calculated as follows: [(number of identical amino acid positions)/(total number of amino acids in the test sequence)] × 100%. Percent identity is calculated to compare test sequence 7: FFFFFYYYYY (SEQ ID NO: 394) (length = 10 amino acids) to reference sequence 8: YYYYYYYYYY (SEQ ID NO: 395) (length = 10 amino acids). The percent identity between test sequence 7 and reference sequence 8 would be [(5)/(10)] ×100% = 50%. Test sequence 7 has 50% sequence identity to reference sequence 8. In another example, percent identity is calculated to compare test sequence 9: LLLLLFFFFFYYYYYLLLLL (SEQ ID NO: 396) (length = 20 amino acids) to reference sequence 10: FFFFFYYYYY (SEQ ID NO: 394) (length = 10 amino acids). The percent identity between test sequence 9 and reference sequence 10 would be [(10)/(20)] ×100% = 50%. Test sequence 9 has 50% sequence identity to reference sequence 10. In another example, percent identity is calculated to compare test sequence 11: FFFFFYYYYY (SEQ ID NO: 394) (length = 10 amino acids) to reference sequence 12: LLLLLFFFFFYYYYYLLLLL (SEQ ID NO: 396) (length = 20 amino acids). The percent identity between test sequence 11 and reference sequence 12 would be [(10)/(10)] ×100% = 100%. Test sequence 11 has 100% sequence identity to reference sequence 12. [0472] For purposes herein, reference to a polynucleotide sequence (e.g., a DNA sequence or an RNA sequence) also encompasses the reverse complement of the polynucleotide sequence. For example, a sequence of AAAAAGGGGG (SEQ ID NO: 390) also encompasses a sequence of CCCCCTTTTT (SEQ ID NO: 397). -202- ^{Docket No. 421688-718021 (718WO1)} [0473] As used herein, the term “subject” broadly refers to any animal, including but not limited to, human and non-human animals (e.g., dogs, cats, cows, horses, sheep, pigs, poultry, fish, crustaceans, etc.). [0474] As used herein, the term “effective amount” refers to the amount of a composition (e.g., a synthetic peptide) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. [0475] As used herein, the term “therapeutically effective amount” is an amount that is effective to ameliorate a symptom of a disease. A therapeutically effective amount can be a “prophylactically effective amount” as prophylaxis can be considered therapy. [0476] As used herein, the terms “administration” and “administering” refer to the act of giving a drug, prodrug, or other agent, or therapeutic treatment (e.g., peptide) to a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs. Exemplary routes of administration to the human body can be through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal or lingual), ear, rectal, vaginal, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.) and the like. [0477] As used herein, the term “treatment” means an approach to obtaining a beneficial or intended clinical result. The beneficial or intended clinical result can include alleviation of symptoms, a reduction in the severity of the disease, inhibiting an underlying cause of a disease or condition, steadying diseases in a non-advanced state, delaying the progress of a disease, and/or improvement or alleviation of disease conditions. [0478] As used herein, the term “pharmaceutical composition” refers to the combination of an active ingredient with a carrier, inert or active, making the composition especially suitable for therapeutic or diagnostic use in vitro, in vivo or ex vivo. [0479] The terms “pharmaceutically acceptable” or “pharmacologically acceptable,” as used herein, refer to compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject. [0480] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), glycerol, liquid polyethylene glycols, aprotic solvents such as dimethylsulfoxide, N-methylpyrrolidone and mixtures thereof, and various types of wetting agents, solubilizing agents, anti-oxidants, bulking -203- ^{Docket No. 421688-718021 (718WO1)} agents, protein carriers such as albumins, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 21st Ed., Mack Publ. Co., Easton, Pa. (2005), incorporated herein by reference in its entirety. [0481] As used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. [0482] As used herein, the terms “about” and “approximately,” in reference to a number, is used herein to include numbers that fall within a range of 10%, 5%, or 1% in either direction (greater than or less than) the number unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). Numbered Embodiments [0483] The following embodiments recite non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated as depending from or relating to every previous or subsequent numbered embodiment, independent of their order as listed.1. A recombinant polynucleotide comprising a promoter and a payload, wherein the promoter comprises: an enhancer sequence capable of enhancing transcription of the payload in a tissue of interest; and a core promoter sequence capable of binding to a polymerase; wherein the payload comprises a coding sequence encoding a protein.2. The recombinant polynucleotide of embodiment 1, wherein the tissue of interest is a central nervous system tissue.3. The recombinant polynucleotide of embodiment 2, wherein the transcription is enhanced in the central nervous system tissue as compared to a kidney tissue.4. The recombinant polynucleotide of embodiment 2 or embodiment 3, wherein the transcription is enhanced in the central nervous system tissue as compared to a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.5. The recombinant polynucleotide of any one of embodiments 1-4, wherein the enhancer sequence comprises at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, or a reverse complement thereof; optionally, wherein: a) the enhancer sequence comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, or a reverse complement thereof; or b) the enhancer sequence comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer sequence.6. The -204- ^{Docket No. 421688-718021 (718WO1)} recombinant polynucleotide of any one of embodiments 1-5, wherein the enhancer sequence comprises at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, or a reverse complement thereof; optionally, wherein: a) the enhancer sequence comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, or a reverse complement thereof; or b) the enhancer sequence comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer sequence.7. The recombinant polynucleotide of any one of embodiments 1-6, wherein the enhancer sequence is any one of SEQ ID NO: 1 – SEQ ID NO: 80, or a reverse complement thereof; optionally, wherein: a) the enhancer sequence comprises one or more enhancer sequences are any one of SEQ ID NO: 1 – SEQ ID NO: 80, or a reverse complement thereof; or b) the enhancer sequence comprises one or more enhancer sequences are any one of SEQ ID NO: 1 – SEQ ID NO: 80, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer sequence.8. The recombinant polynucleotide of any one of embodiments 1-7, wherein the enhancer sequence comprises SEQ ID NO: 1, or a reverse complement thereof.9. The recombinant polynucleotide of any one of embodiments 1-8, wherein the enhancer sequence comprises SEQ ID NO: 2, or a reverse complement thereof.10. The recombinant polynucleotide of any one of embodiments 1-9, wherein the enhancer sequence comprises SEQ ID NO: 3, or a reverse complement thereof.11. The recombinant polynucleotide of any one of embodiments 1-10, wherein the enhancer sequence comprises SEQ ID NO: 4, or a reverse complement thereof.12. The recombinant polynucleotide of any one of embodiments 1-11, wherein the enhancer sequence comprises SEQ ID NO: 5, or a reverse complement thereof.13. The recombinant polynucleotide of any one of embodiments 1-12, wherein the enhancer sequence comprises SEQ ID NO: 6, or a reverse complement thereof.14. The recombinant polynucleotide of any one of embodiments 1-13, wherein the enhancer sequence comprises SEQ ID NO: 7, or a reverse complement thereof.15. The recombinant polynucleotide of any one of embodiments 1-14, wherein the enhancer sequence comprises SEQ ID NO: 8, or a reverse complement thereof.16. The recombinant polynucleotide of any one of embodiments 1-15, wherein the enhancer sequence comprises SEQ ID NO: 9, or a reverse complement thereof.17. The recombinant polynucleotide of any one of embodiments 1-16, wherein the enhancer sequence comprises SEQ ID NO: 10, or a reverse complement thereof.18. The recombinant polynucleotide of any one of embodiments 1-17, wherein the enhancer sequence comprises SEQ ID NO: 11, or a reverse complement thereof.19. The recombinant polynucleotide of any one of embodiments 1-18, wherein the enhancer -205- ^{Docket No. 421688-718021 (718WO1)} sequence comprises SEQ ID NO: 12, or a reverse complement thereof.20. The recombinant polynucleotide of any one of embodiments 1-19, wherein the enhancer sequence comprises SEQ ID NO: 13, or a reverse complement thereof.21. The recombinant polynucleotide of any one of embodiments 1-20, wherein the enhancer sequence comprises SEQ ID NO: 14, or a reverse complement thereof.22. The recombinant polynucleotide of any one of embodiments 1-21, wherein the enhancer sequence comprises SEQ ID NO: 15, or a reverse complement thereof.23. The recombinant polynucleotide of any one of embodiments 1-22, wherein the enhancer sequence comprises SEQ ID NO: 16, or a reverse complement thereof.24. The recombinant polynucleotide of any one of embodiments 1-23, wherein the enhancer sequence comprises SEQ ID NO: 17, or a reverse complement thereof.25. The recombinant polynucleotide of any one of embodiments 1-24, wherein the enhancer sequence comprises SEQ ID NO: 18, or a reverse complement thereof.26. The recombinant polynucleotide of any one of embodiments 1-25, wherein the enhancer sequence comprises SEQ ID NO: 19, or a reverse complement thereof.27. The recombinant polynucleotide of any one of embodiments 1-26, wherein the enhancer sequence comprises SEQ ID NO: 20, or a reverse complement thereof.28. The recombinant polynucleotide of any one of embodiments 1-27, wherein the enhancer sequence comprises two or more of SEQ ID NO: 1 – SEQ ID NO: 20.29. The recombinant polynucleotide of any one of embodiments 1-28, wherein the enhancer sequence comprises a duplication of any one of SEQ ID NO: 1 – SEQ ID NO: 20.30. The recombinant polynucleotide of any one of embodiments 1- 29, wherein the core promoter sequence comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, or a YB_TATA promoter.31. The recombinant polynucleotide of any one of embodiments 1-30, wherein the core promoter sequence comprises any one of SEQ ID NO: 81 – SEQ ID NO: 236; optionally, wherein the core promoter sequence comprises SEQ ID NO: 95.32. The recombinant polynucleotide of any one of embodiments 1-31, wherein the payload encodes a protein.33. The recombinant polynucleotide of embodiment 32, wherein the protein is a neuronal protein.34. The recombinant polynucleotide of embodiment 32 or embodiment 33, wherein the protein is associated with a central nervous system disorder.35. The recombinant polynucleotide of embodiment 34, wherein the central nervous system disorder is a neuronal disorder.36. The recombinant polynucleotide of embodiment 34 or embodiment 35, wherein the central nervous system disorder is a genetic disorder.37. The recombinant polynucleotide of any one of embodiments 32-36, wherein the protein is progranulin or MeCP2.38. The recombinant polynucleotide of any one of embodiments 1-31, wherein the payload encodes a therapeutic polynucleotide.39. The recombinant polynucleotide of embodiment 38, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.40. The recombinant polynucleotide of -206- ^{Docket No. 421688-718021 (718WO1)} embodiment 38 or embodiment 39, wherein the therapeutic polynucleotide targets a gene.41. The recombinant polynucleotide of embodiment 40, wherein the gene is associated with a central nervous system disorder.42. The recombinant polynucleotide of embodiment 41, wherein the central nervous system disorder is a neuronal disorder.43. The recombinant polynucleotide of embodiment 41 or embodiment 42, wherein the central nervous system disorder is a genetic disorder.44. The recombinant polynucleotide of any one of embodiments 40-43, wherein the gene is GRN or MECP2.45. An engineered viral vector comprising the recombinant polynucleotide of any one of embodiments 1-44 in a viral vector.46. The engineered viral vector of embodiment 45, wherein the viral vector is an adenoviral vector, an adeno-associated viral vector, or a lentivector.47. The engineered viral vector of embodiment 46, wherein the adeno-associated viral vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV-DJ, AAV-DJ/8, AAV-DJ/9, AAV1/2, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh43, AAV.Rh74, AAV.v66, AAV.Oligo001, AAV.SCH9, AAV.r3.45, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PhP.eB, AAV.PhP.V1, AAV.PHP.B, AAV.PhB.C1, AAV.PhB.C2, AAV.PhB.C3, AAV.PhB.C6, AAV.cy5, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAV.HSC17, AAVhu68, and combinations thereof.48. A pharmaceutical composition comprising the recombinant polynucleotide of any one of embodiments 1-44 or the engineered viral vector of any one of embodiments 45-47 and a pharmaceutically acceptable carrier.49. A method of expressing a payload in a target tissue of a subject, the method comprising: administering to the subject the recombinant polynucleotide of any one of embodiments 1-44, the engineered viral vector of any one of embodiments 45-47, or the pharmaceutical composition of embodiment 48 to the subject; and transcribing the payload in the target tissue.50. The method of embodiment 49, wherein the target tissue is a central nervous system tissue.51. The method of embodiment 49 or embodiment 50, comprising expressing the payload at a higher level in the target tissue than in a non-target tissue.52. The method of embodiment 51, wherein the non-target tissue is a kidney tissue, a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.53. The method of embodiment 51 or embodiment 52, wherein the target tissue a target cell type, and wherein the non-target tissue comprises a non-target cell type.54. The method of embodiment 53, wherein the target cell type is a neuron or a glial cell.55. The method of embodiment 53 or embodiment 54, wherein the non-target cell type is a renal cell, a retinal cell, a hepatocyte, an epithelial cell, a muscle cell, an erythrocyte, a platelet, a bone marrow cell, an endothelial cell, an epidermal cell, -207- ^{Docket No. 421688-718021 (718WO1)} a lymphocyte, an interstitial cell, an adipocyte, a fibroblast, or combinations thereof.56. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising the recombinant polynucleotide of any one of embodiments 1-44, the engineered viral vector of any one of embodiments 45-47, or the pharmaceutical composition of embodiment 48 to the subject; and expressing a therapeutic sequence encoded by a payload of the recombinant polynucleotide in a target tissue of the subject, thereby treating the disorder.57. The method of embodiment 56, wherein the target tissue is associated with the disorder.58. The method of embodiment 56 or embodiment 57, wherein the disorder is a central nervous system disorder.59. The method of embodiment 58, wherein the central nervous system disorder is a neuronal disorder.60. The method of embodiment 58 or embodiment 59, wherein the central nervous system disorder is a genetic disorder.61. The method of any one of embodiments 58-60, wherein the disorder is Rett syndrome, MECP2 duplication syndrome, frontotemporal dementia, neuronal ceroid lipofuscinosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson’s disease.62. The method of any one of embodiments 56-61, wherein the disorder is any one of the disorders provided in TABLE 3.63. The method of any one of embodiments 56-62, wherein the therapeutic sequence encodes a therapeutic protein.64. The method of embodiment 63, wherein the therapeutic protein is a neuronal protein.65. The method of embodiment 63 or embodiment 64, wherein the therapeutic protein is associated with a central nervous system disorder.66. The method of embodiment 65, wherein the central nervous system disorder is a neuronal disorder. 67. The method of embodiment 65 or embodiment 66, wherein the central nervous system disorder is a genetic disorder.68. The method of any one of embodiments 63-67, wherein the therapeutic protein is MECP2 or progranulin.69. The method of any one of embodiments 63-68, wherein the therapeutic protein is encoded by a gene provided in TABLE 3.70. The method of any one of embodiments 56-62, wherein the payload encodes a therapeutic polynucleotide.71. The method of embodiment 70, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.72. The method of embodiment 70 or embodiment 71, wherein the therapeutic polynucleotide targets a gene provided in TABLE 3. Further Numbered Embodiments [0484] The following embodiments recite non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated as depending from or relating to every previous or subsequent numbered embodiment, independent of their order as listed.1. A recombinant polynucleotide comprising a promoter and a payload, wherein the promoter -208- ^{Docket No. 421688-718021 (718WO1)} comprises: an enhancer capable of enhancing transcription of the payload in a tissue of interest; and a core promoter capable of binding to a polymerase; wherein the payload comprises a coding sequence encoding a protein.2. The recombinant polynucleotide of embodiment 1, wherein the tissue of interest is a central nervous system tissue.3. The recombinant polynucleotide of embodiment 2, wherein the transcription is enhanced in the central nervous system tissue as compared to a kidney tissue.4. The recombinant polynucleotide of embodiment 2 or embodiment 3, wherein the transcription is enhanced in the central nervous system tissue as compared to a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.5. The recombinant polynucleotide of any one of embodiments 1-4, wherein the enhancer comprises a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.6. The recombinant polynucleotide of any one of embodiments 1-5, wherein the enhancer comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.7. The recombinant polynucleotide of any one of embodiments 1-6, wherein the enhancer comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer.8. The recombinant polynucleotide of any one of embodiments 1- 7, wherein the enhancer comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.9. The recombinant polynucleotide of any one of embodiments 1-8, wherein the enhancer comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.10. The recombinant polynucleotide of any one of embodiments 1-9, wherein the enhancer comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer.11. The recombinant polynucleotide of any one of embodiments 1-10, wherein the enhancer comprises any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.12. The recombinant polynucleotide of any one of embodiments 1- 10, wherein the enhancer comprises one or more enhancer sequences selected from SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof. 13. The recombinant polynucleotide of any one of embodiments 1-11, wherein the enhancer -209- ^{Docket No. 421688-718021 (718WO1)} comprises one or more enhancer sequences selected from SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer.14. The recombinant polynucleotide of any one of embodiments 1-13, wherein the enhancer comprises SEQ ID NO: 1, or a reverse complement thereof.15. The recombinant polynucleotide of any one of embodiments 1-14, wherein the enhancer comprises SEQ ID NO: 2, or a reverse complement thereof.16. The recombinant polynucleotide of any one of embodiments 1-15, wherein the enhancer comprises SEQ ID NO: 3, or a reverse complement thereof.17. The recombinant polynucleotide of any one of embodiments 1-16, wherein the enhancer comprises SEQ ID NO: 4, or a reverse complement thereof.18. The recombinant polynucleotide of any one of embodiments 1-17, wherein the enhancer comprises SEQ ID NO: 5, or a reverse complement thereof.19. The recombinant polynucleotide of any one of embodiments 1-18, wherein the enhancer comprises SEQ ID NO: 6, or a reverse complement thereof.20. The recombinant polynucleotide of any one of embodiments 1-19, wherein the enhancer comprises SEQ ID NO: 7, or a reverse complement thereof.21. The recombinant polynucleotide of any one of embodiments 1-20, wherein the enhancer comprises SEQ ID NO: 8, or a reverse complement thereof.22. The recombinant polynucleotide of any one of embodiments 1-21, wherein the enhancer comprises SEQ ID NO: 9, or a reverse complement thereof.23. The recombinant polynucleotide of any one of embodiments 1-22, wherein the enhancer comprises SEQ ID NO: 10, or a reverse complement thereof.24. The recombinant polynucleotide of any one of embodiments 1-23, wherein the enhancer comprises SEQ ID NO: 11, or a reverse complement thereof.25. The recombinant polynucleotide of any one of embodiments 1-24, wherein the enhancer comprises SEQ ID NO: 12, or a reverse complement thereof.26. The recombinant polynucleotide of any one of embodiments 1-25, wherein the enhancer comprises SEQ ID NO: 13, or a reverse complement thereof.27. The recombinant polynucleotide of any one of embodiments 1-26, wherein the enhancer comprises SEQ ID NO: 14, or a reverse complement thereof.28. The recombinant polynucleotide of any one of embodiments 1-27, wherein the enhancer comprises SEQ ID NO: 15, or a reverse complement thereof.29. The recombinant polynucleotide of any one of embodiments 1-28, wherein the enhancer comprises SEQ ID NO: 16, or a reverse complement thereof.30. The recombinant polynucleotide of any one of embodiments 1-29, wherein the enhancer comprises SEQ ID NO: 17, or a reverse complement thereof.31. The recombinant polynucleotide of any one of embodiments 1-30, wherein the enhancer comprises SEQ ID NO: 18, or a reverse complement thereof.32. The recombinant polynucleotide of any one of embodiments 1-31, wherein the enhancer comprises SEQ ID NO: 19, or a reverse complement thereof.33. The recombinant polynucleotide of any one of -210- ^{Docket No. 421688-718021 (718WO1)} embodiments 1-32, wherein the enhancer comprises SEQ ID NO: 20, or a reverse complement thereof.34. The recombinant polynucleotide of any one of embodiments 1-33, wherein the enhancer comprises two or more of SEQ ID NO: 1 – SEQ ID NO: 20.35. The recombinant polynucleotide of embodiment 34, wherein the enhancer comprises any one of SEQ ID NO: 237 – SEQ ID NO: 266.36. The recombinant polynucleotide of embodiment 34 or embodiment 35, wherein the enhancer comprises SEQ ID NO: 244.37. The recombinant polynucleotide of any one of embodiments 1-36, wherein the enhancer comprises a duplication of any one of SEQ ID NO: 1 – SEQ ID NO: 20.38. The recombinant polynucleotide of embodiment 37, wherein the enhancer comprises any one of SEQ ID NO: 267 – SEQ ID NO: 286.39. The recombinant polynucleotide of any one of embodiments 1-38, wherein the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, or a YB_TATA promoter.40. The recombinant polynucleotide of any one of embodiments 1-39, wherein the core promoter comprises any one of SEQ ID NO: 81 – SEQ ID NO: 236.41. The recombinant polynucleotide of any one of embodiments 1-40, wherein the core promoter comprises SEQ ID NO: 95.42. The recombinant polynucleotide of any one of embodiments 1- 41, wherein the payload encodes a protein.43. The recombinant polynucleotide of embodiment 42, wherein the protein is a neuronal protein.44. The recombinant polynucleotide of embodiment 42 or embodiment 43, wherein the protein is associated with a central nervous system disorder.45. The recombinant polynucleotide of embodiment 44, wherein the central nervous system disorder is a neuronal disorder.46. The recombinant polynucleotide of embodiment 44 or embodiment 45, wherein the central nervous system disorder is a genetic disorder.47. The recombinant polynucleotide of any one of embodiments 42-46, wherein the protein is progranulin or MeCP2.48. The recombinant polynucleotide of any one of embodiments 1-41, wherein the payload encodes a therapeutic polynucleotide.49. The recombinant polynucleotide of embodiment 48, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.50. The recombinant polynucleotide of embodiment 48 or embodiment 49, wherein the therapeutic polynucleotide targets a gene.51. The recombinant polynucleotide of embodiment 50, wherein the gene is associated with a central nervous system disorder.52. The recombinant polynucleotide of embodiment 51, wherein the central nervous system disorder is a neuronal disorder.53. The recombinant polynucleotide of embodiment 51 or embodiment 52, wherein the central nervous system disorder is a genetic disorder.54. The recombinant polynucleotide of any one of embodiments 50-53, wherein the gene is GRN or MECP2.55. An engineered viral vector comprising the recombinant polynucleotide of any one of embodiments 1-54 in a viral vector.56. The engineered viral vector of embodiment 55, wherein the viral vector is an adenoviral vector, an adeno-associated viral vector, or a -211- ^{Docket No. 421688-718021 (718WO1)} lentivector.57. The engineered viral vector of embodiment 56, wherein the adeno-associated viral vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV-DJ, AAV-DJ/8, AAV-DJ/9, AAV1/2, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh43, AAV.Rh74, AAV.v66, AAV.Oligo001, AAV.SCH9, AAV.r3.45, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PhP.eB, AAV.PhP.V1, AAV.PHP.B, AAV.PhB.C1, AAV.PhB.C2, AAV.PhB.C3, AAV.PhB.C6, AAV.cy5, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAV.HSC17, AAVhu68, and combinations thereof.58. A pharmaceutical composition comprising the recombinant polynucleotide of any one of embodiments 1-54 or the engineered viral vector of any one of embodiments 55-57 and a pharmaceutically acceptable carrier.59. A method of expressing a payload in a target tissue of a subject, the method comprising: administering to the subject the recombinant polynucleotide of any one of embodiments 1-54, the engineered viral vector of any one of embodiments 55-57, or the pharmaceutical composition of embodiment 58 to the subject; and transcribing the payload in the target tissue.60. The method of embodiment 59, wherein the target tissue is a central nervous system tissue.61. The method of embodiment 59 or embodiment 60, comprising expressing the payload at a higher level in the target tissue than in a non-target tissue.62. The method of embodiment 61, wherein the non-target tissue is a kidney tissue, a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.63. The method of embodiment 61 or embodiment 62, wherein the target tissue a target cell type, and wherein the non-target tissue comprises a non- target cell type.64. The method of embodiment 63, wherein the target cell type is a neuron or a glial cell.65. The method of embodiment 63 or embodiment 64, wherein the non-target cell type is a renal cell, a retinal cell, a hepatocyte, an epithelial cell, a muscle cell, an erythrocyte, a platelet, a bone marrow cell, an endothelial cell, an epidermal cell, a lymphocyte, an interstitial cell, an adipocyte, a fibroblast, or combinations thereof.66. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising the recombinant polynucleotide of any one of embodiments 1-51, the engineered viral vector of any one of embodiments 52-57, or the pharmaceutical composition of embodiment 58 to the subject; and expressing a therapeutic sequence encoded by a payload of the recombinant polynucleotide in a target tissue of the subject, thereby treating the disorder.67. The method of embodiment 66, wherein the target tissue is associated with the disorder.68. The method of embodiment 66 or embodiment 67, wherein the disorder is a central nervous system disorder.69. The method of embodiment 68, wherein the central nervous system disorder is a -212- ^{Docket No. 421688-718021 (718WO1)} neuronal disorder.70. The method of embodiment 68 or embodiment 69, wherein the central nervous system disorder is a genetic disorder.71. The method of any one of embodiments 68-70, wherein the disorder is Rett syndrome, MECP2 duplication syndrome, frontotemporal dementia, neuronal ceroid lipofuscinosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson’s disease.72. The method of any one of embodiments 66-71, wherein the disorder is any one of the disorders provided in TABLE 3.73. The method of any one of embodiments 66-72, wherein the therapeutic sequence encodes a therapeutic protein.74. The method of embodiment 73, wherein the therapeutic protein is a neuronal protein.75. The method of embodiment 73 or embodiment 74, wherein the therapeutic protein is associated with a central nervous system disorder.76. The method of embodiment 75, wherein the central nervous system disorder is a neuronal disorder.77. The method of embodiment 75 or embodiment 76, wherein the central nervous system disorder is a genetic disorder.78. The method of any one of embodiments 73-77, wherein the therapeutic protein is MECP2 or progranulin.79. The method of any one of embodiments 73-78, wherein the therapeutic protein is encoded by a gene provided in TABLE 3. 80. The method of any one of embodiments 66-72, wherein the payload encodes a therapeutic polynucleotide.81. The method of embodiment 80, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.82. The method of embodiment 80 or embodiment 81, wherein the therapeutic polynucleotide targets a gene provided in TABLE 3. Further Numbered Embodiments [0485] The following embodiments recite non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated as depending from or relating to every previous or subsequent numbered embodiment, independent of their order as listed.1. A recombinant polynucleotide comprising a promoter and a payload, wherein the promoter comprises: an enhancer capable of enhancing transcription of the payload in a tissue of interest; and a core promoter capable of binding to a polymerase; wherein the payload comprises a coding sequence encoding a protein.2. The recombinant polynucleotide of embodiment 1, wherein the tissue of interest is a central nervous system tissue.3. The recombinant polynucleotide of embodiment 2, wherein the transcription is enhanced in the central nervous system tissue as compared to a kidney tissue.4. The recombinant polynucleotide of embodiment 2 or embodiment 3, wherein the transcription is enhanced in the central nervous system tissue as compared to a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.5. The recombinant polynucleotide of any one of embodiments 1-4, wherein the enhancer comprises a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID -213- ^{Docket No. 421688-718021 (718WO1)} NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.6. The recombinant polynucleotide of any one of embodiments 1-5, wherein the enhancer comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.7. The recombinant polynucleotide of any one of embodiments 1-6, wherein the enhancer comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer.8. The recombinant polynucleotide of any one of embodiments 1- 7, wherein the enhancer comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.9. The recombinant polynucleotide of any one of embodiments 1-8, wherein the enhancer comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.10. The recombinant polynucleotide of any one of embodiments 1-9, wherein the enhancer comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer.11. The recombinant polynucleotide of any one of embodiments 1-10, wherein the enhancer comprises any one of SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof.12. The recombinant polynucleotide of any one of embodiments 1- 10, wherein the enhancer comprises one or more enhancer sequences selected from SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof. 13. The recombinant polynucleotide of any one of embodiments 1-11, wherein the enhancer comprises one or more enhancer sequences selected from SEQ ID NO: 1 – SEQ ID NO: 80 or SEQ ID NO: 237 – SEQ ID NO: 286, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer.14. The recombinant polynucleotide of any one of embodiments 1-13, wherein the enhancer comprises SEQ ID NO: 1, or a reverse complement thereof.15. The recombinant polynucleotide of any one of embodiments 1-14, wherein the enhancer comprises SEQ ID NO: 2, or a reverse complement thereof.16. The recombinant polynucleotide of any one of embodiments 1-15, wherein the enhancer comprises SEQ ID NO: 3, or a reverse complement thereof.17. The recombinant polynucleotide of any one of embodiments 1-16, wherein the enhancer comprises SEQ ID NO: 4, or a reverse complement thereof.18. The recombinant polynucleotide of any one -214- ^{Docket No. 421688-718021 (718WO1)} of embodiments 1-17, wherein the enhancer comprises SEQ ID NO: 5, or a reverse complement thereof.19. The recombinant polynucleotide of any one of embodiments 1-18, wherein the enhancer comprises SEQ ID NO: 6, or a reverse complement thereof.20. The recombinant polynucleotide of any one of embodiments 1-19, wherein the enhancer comprises SEQ ID NO: 7, or a reverse complement thereof.21. The recombinant polynucleotide of any one of embodiments 1-20, wherein the enhancer comprises SEQ ID NO: 8, or a reverse complement thereof.22. The recombinant polynucleotide of any one of embodiments 1-21, wherein the enhancer comprises SEQ ID NO: 9, or a reverse complement thereof.23. The recombinant polynucleotide of any one of embodiments 1-22, wherein the enhancer comprises SEQ ID NO: 10, or a reverse complement thereof.24. The recombinant polynucleotide of any one of embodiments 1-23, wherein the enhancer comprises SEQ ID NO: 11, or a reverse complement thereof.25. The recombinant polynucleotide of any one of embodiments 1-24, wherein the enhancer comprises SEQ ID NO: 12, or a reverse complement thereof.26. The recombinant polynucleotide of any one of embodiments 1-25, wherein the enhancer comprises SEQ ID NO: 13, or a reverse complement thereof.27. The recombinant polynucleotide of any one of embodiments 1-26, wherein the enhancer comprises SEQ ID NO: 14, or a reverse complement thereof.28. The recombinant polynucleotide of any one of embodiments 1-27, wherein the enhancer comprises SEQ ID NO: 15, or a reverse complement thereof.29. The recombinant polynucleotide of any one of embodiments 1-28, wherein the enhancer comprises SEQ ID NO: 16, or a reverse complement thereof.30. The recombinant polynucleotide of any one of embodiments 1-29, wherein the enhancer comprises SEQ ID NO: 17, or a reverse complement thereof.31. The recombinant polynucleotide of any one of embodiments 1-30, wherein the enhancer comprises SEQ ID NO: 18, or a reverse complement thereof.32. The recombinant polynucleotide of any one of embodiments 1-31, wherein the enhancer comprises SEQ ID NO: 19, or a reverse complement thereof.33. The recombinant polynucleotide of any one of embodiments 1-32, wherein the enhancer comprises SEQ ID NO: 20, or a reverse complement thereof.34. The recombinant polynucleotide of any one of embodiments 1-33, wherein the enhancer comprises two or more of SEQ ID NO: 1 – SEQ ID NO: 20.35. The recombinant polynucleotide of embodiment 34, wherein the enhancer comprises any one of SEQ ID NO: 237 – SEQ ID NO: 266.36. The recombinant polynucleotide of embodiment 34 or embodiment 35, wherein the enhancer comprises SEQ ID NO: 244.37. The recombinant polynucleotide of any one of embodiments 1-36, wherein the enhancer comprises a duplication of any one of SEQ ID NO: 1 – SEQ ID NO: 20.38. The recombinant polynucleotide of embodiment 37, wherein the enhancer comprises any one of SEQ ID NO: 267 – SEQ ID NO: 286.39. The recombinant polynucleotide of any one of embodiments 1-38, wherein the core promoter comprises a TATA -215- ^{Docket No. 421688-718021 (718WO1)} box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, or a YB_TATA promoter.40. The recombinant polynucleotide of any one of embodiments 1-39, wherein the core promoter comprises any one of SEQ ID NO: 81 – SEQ ID NO: 236.41. The recombinant polynucleotide of any one of embodiments 1-40, wherein the core promoter comprises SEQ ID NO: 95.42. The recombinant polynucleotide of any one of embodiments 1- 41, further comprising a post-transcriptional regulatory element.43. The recombinant polynucleotide of embodiment 42, wherein the post-transcriptional regulatory element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 287 or SEQ ID NO: 288.44. The recombinant polynucleotide of any one of embodiments 1-43, further comprising a neuron-restrictive silencer element.45. The recombinant polynucleotide of embodiment 44, wherein the neuron-restrictive silencer element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296.46. The recombinant polynucleotide of any one of embodiments 1-45, further comprising a polyadenylation signal.47. The recombinant polynucleotide of embodiment 46, wherein the polyadenylation signal comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306.48. The recombinant polynucleotide of any one of embodiments 1-47, further comprising a transcriptional pause site.49. The recombinant polynucleotide of embodiment 48, wherein the transcriptional pause site comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 311.50. The recombinant polynucleotide of any one of embodiments 1-49, further comprising a CCCTC-binding factor sequence.51. The recombinant polynucleotide of embodiment 50, wherein the CCCTC-binding factor sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295.52. The recombinant polynucleotide of any one of embodiments 1-51, further comprising a stuffer sequence.53. The recombinant polynucleotide of embodiment 52, wherein the stuffer sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 309.54. The recombinant polynucleotide of any one of embodiments 1-53, comprising a 5’ untranslated region.55. The recombinant polynucleotide of embodiment 54, wherein the 5’ untranslated region comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 310, SEQ ID NO: 353, or SEQ ID NO: 354.56. The recombinant polynucleotide of any one of embodiments 1-55, further comprising a 5’ inverted terminal repeat.57. The recombinant polynucleotide of embodiment 56, wherein the 5’ inverted terminal -216- ^{Docket No. 421688-718021 (718WO1)} repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 307.58. The recombinant polynucleotide of any one of embodiments 1-57, further comprising a 3’ inverted terminal repeat.59. The recombinant polynucleotide of embodiment 58, wherein the 3’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 308.60. The recombinant polynucleotide of any one of embodiments 1- 59, comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 312.61. The recombinant polynucleotide of any one of embodiments 1-60, wherein the payload encodes a protein.62. The recombinant polynucleotide of embodiment 61, wherein the protein is a neuronal protein.63. The recombinant polynucleotide of embodiment 61 or embodiment 62, wherein the protein is associated with a central nervous system disorder.64. The recombinant polynucleotide of embodiment 63, wherein the central nervous system disorder is a neuronal disorder.65. The recombinant polynucleotide of embodiment 63 or embodiment 64, wherein the central nervous system disorder is a genetic disorder.66. The recombinant polynucleotide of any one of embodiments 61-65, wherein the protein is progranulin or MeCP2.67. The recombinant polynucleotide of embodiment 66, wherein the progranulin encoded by the payload comprises at least 90% sequence identity to SEQ ID NO: 352.68. The recombinant polynucleotide of any one of embodiments 1-60, wherein the payload encodes a therapeutic polynucleotide.69. The recombinant polynucleotide of embodiment 68, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.70. The recombinant polynucleotide of embodiment 68 or embodiment 69, wherein the therapeutic polynucleotide targets a gene.71. The recombinant polynucleotide of embodiment 70, wherein the gene is associated with a central nervous system disorder.72. The recombinant polynucleotide of embodiment 71, wherein the central nervous system disorder is a neuronal disorder.73. The recombinant polynucleotide of embodiment 71 or embodiment 72, wherein the central nervous system disorder is a genetic disorder.74. The recombinant polynucleotide of any one of embodiments 70-73, wherein the gene is GRN or MECP2.75. A plasmid comprising the recombinant polynucleotide of any one of embodiments 1-74.76. The plasmid of embodiment 75, comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 355.77. An engineered viral vector comprising the recombinant polynucleotide of any one of embodiments 1-74 or the plasmid of embodiment 75 or embodiment 76 in a viral vector.78. The engineered viral vector of embodiment 77, wherein the viral vector is an adenoviral vector, an adeno- associated viral vector, or a lentivector.79. The engineered viral vector of embodiment 78, wherein the adeno-associated viral vector is selected from the group consisting of AAV1, AAV2, -217- ^{Docket No. 421688-718021 (718WO1)} AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV-DJ, AAV-DJ/8, AAV-DJ/9, AAV1/2, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh43, AAV.Rh74, AAV.v66, AAV.Oligo001, AAV.SCH9, AAV.r3.45, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PhP.eB, AAV.PhP.V1, AAV.PHP.B, AAV.PhB.C1, AAV.PhB.C2, AAV.PhB.C3, AAV.PhB.C6, AAV.cy5, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAV.HSC17, AAVhu68, and combinations thereof.80. The engineered viral vector of embodiment 78 or embodiment 79, wherein the adeno-associated viral vector is an AAV5 vector.81. The engineered viral vector of any one of embodiments 78-80, wherein the adeno-associated viral vector comprises an engineered viral protein (VP) capsid polypeptide.82. The engineered viral vector of embodiment 81, wherein the engineered VP capsid polypeptide comprises at least one substitution in a 581-589 region of the engineered VP capsid polypeptide relative to a wild type VP capsid polypeptide of SEQ ID NO: 313.83. The engineered viral vector of embodiment 82, wherein the 581-589 region comprises a sequence of any one of SEQ ID NO: 320 – SEQ ID NO: 349.84. The engineered viral vector of embodiment 82 or embodiment 83, wherein the 581-589 region comprises a sequence of SEQ ID NO: 321.85. The engineered viral vector of embodiment 82 or embodiment 83, wherein the 581-589 region comprises a sequence of SEQ ID NO: 322.86. The engineered viral vector of embodiment 82 or embodiment 83, wherein the 581-589 region comprises a sequence of SEQ ID NO: 320.87. The engineered viral vector of embodiment 82 or embodiment 83, wherein the 581-589 region comprises a sequence of SEQ ID NO: 334.88. The engineered viral vector of any one of embodiments 82-87, wherein the engineered VP capsid polypeptide comprises a formula of (A)-(X)-(B), wherein (A) is a first polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 318, (X) is the 581-589 region, and (B) is a second polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 319.89. A pharmaceutical composition comprising the recombinant polynucleotide of any one of embodiments 1-74, the plasmid of embodiment 75 or embodiment 76, or the engineered viral vector of any one of embodiments 77-88 and a pharmaceutically acceptable carrier.90. A method of expressing a payload in a target tissue of a subject, the method comprising: administering to the subject the recombinant polynucleotide of any one of embodiments 1-74, the plasmid of embodiment 75 or embodiment 76, the engineered viral vector of any one of embodiments 77-88, or the pharmaceutical composition of embodiment 89 to the subject; and transcribing the payload in the target tissue. -218- ^{Docket No. 421688-718021 (718WO1)} 91. The method of embodiment 90, wherein the target tissue is a central nervous system tissue. 92. The method of embodiment 90 or embodiment 91, comprising expressing the payload at a higher level in the target tissue than in a non-target tissue.93. The method of embodiment 92, wherein the non-target tissue is a kidney tissue, a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.94. The method of embodiment 92 or embodiment 93, wherein the target tissue a target cell type, and wherein the non-target tissue comprises a non-target cell type.95. The method of embodiment 94, wherein the target cell type is a neuron or a glial cell.96. The method of embodiment 94 or embodiment 95, wherein the non-target cell type is a renal cell, a retinal cell, a hepatocyte, an epithelial cell, a muscle cell, an erythrocyte, a platelet, a bone marrow cell, an endothelial cell, an epidermal cell, a lymphocyte, an interstitial cell, an adipocyte, a fibroblast, or combinations thereof.97. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising the recombinant polynucleotide of any one of embodiments 1-74, the plasmid of embodiment 75 or embodiment 76, the engineered viral vector of any one of embodiments 77-88, or the pharmaceutical composition of embodiment 89 to the subject; and expressing a therapeutic sequence encoded by a payload of the recombinant polynucleotide in a target tissue of the subject, thereby treating the disorder.98. The method of embodiment 97, wherein the target tissue is associated with the disorder.99. The method of embodiment 97 or embodiment 98, wherein the disorder is a central nervous system disorder.100. The method of embodiment 99, wherein the central nervous system disorder is a neuronal disorder.101. The method of embodiment 99 or embodiment 100, wherein the central nervous system disorder is a genetic disorder.102. The method of any one of embodiments 99-101, wherein the disorder is Rett syndrome, MECP2 duplication syndrome, frontotemporal dementia, neuronal ceroid lipofuscinosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson’s disease.103. The method of any one of embodiments 99-102, wherein the disorder is any one of the disorders provided in TABLE 3.104. The method of any one of embodiments 99-103, wherein the therapeutic sequence encodes a therapeutic protein.105. The method of embodiment 104, wherein the therapeutic protein is a neuronal protein.106. The method of embodiment 104 or embodiment 105, wherein the therapeutic protein is associated with a central nervous system disorder.107. The method of embodiment 106, wherein the central nervous system disorder is a neuronal disorder.108. The method of embodiment 106 or embodiment 104, wherein the central nervous system disorder is a genetic disorder.109. The method of any one of embodiments 104- 108, wherein the therapeutic protein is MECP2 or progranulin.110. The method of any one of embodiments 104-109, wherein the therapeutic protein is encoded by a gene provided in TABLE 3.111. The method of any one of embodiments 99-103, wherein the payload encodes a -219- ^{Docket No. 421688-718021 (718WO1)} therapeutic polynucleotide.112. The method of embodiment 111, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.113. The method of embodiment 111 or embodiment 112, wherein the therapeutic polynucleotide targets a gene provided in TABLE 3. Further Numbered Embodiments [0486] The following embodiments recite non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated as depending from or relating to every previous or subsequent numbered embodiment, independent of their order as listed.1. A recombinant polynucleotide comprising a promoter and a payload, wherein the promoter comprises: an enhancer capable of enhancing transcription of the payload in a tissue of interest; and a core promoter capable of binding to a polymerase; wherein the payload comprises a coding sequence encoding a protein.2. The recombinant polynucleotide of embodiment 1, wherein the tissue of interest is a central nervous system tissue.3. The recombinant polynucleotide of embodiment 2, wherein the transcription is enhanced in the central nervous system tissue as compared to a kidney tissue.4. The recombinant polynucleotide of embodiment 2 or embodiment 3, wherein the transcription is enhanced in the central nervous system tissue as compared to a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.5. The recombinant polynucleotide of any one of embodiments 1-4, wherein the enhancer comprises a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof.6. The recombinant polynucleotide of any one of embodiments 1-5, wherein the enhancer comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof.7. The recombinant polynucleotide of any one of embodiments 1-6, wherein the enhancer comprises one or more enhancer sequences having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer.8. The recombinant polynucleotide of any one of embodiments 1-7, wherein the enhancer comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof.9. The recombinant polynucleotide of any one of embodiments 1-8, wherein the enhancer comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ -220- ^{Docket No. 421688-718021 (718WO1)} ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof.10. The recombinant polynucleotide of any one of embodiments 1- 9, wherein the enhancer comprises one or more enhancer sequences having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer.11. The recombinant polynucleotide of any one of embodiments 1-10, wherein the enhancer comprises any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof.12. The recombinant polynucleotide of any one of embodiments 1-10, wherein the enhancer comprises one or more enhancer sequences selected from SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof.13. The recombinant polynucleotide of any one of embodiments 1-11, wherein the enhancer comprises one or more enhancer sequences selected from SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, wherein the one or more enhancer sequences are duplicated or repeated at least 2, 3, 4, or more times in the enhancer.14. The recombinant polynucleotide of any one of embodiments 1-13, wherein the enhancer comprises SEQ ID NO: 1, or a reverse complement thereof.15. The recombinant polynucleotide of any one of embodiments 1-14, wherein the enhancer comprises SEQ ID NO: 2, or a reverse complement thereof.16. The recombinant polynucleotide of any one of embodiments 1-15, wherein the enhancer comprises SEQ ID NO: 3, or a reverse complement thereof.17. The recombinant polynucleotide of any one of embodiments 1-16, wherein the enhancer comprises SEQ ID NO: 4, or a reverse complement thereof.18. The recombinant polynucleotide of any one of embodiments 1-17, wherein the enhancer comprises SEQ ID NO: 5, or a reverse complement thereof.19. The recombinant polynucleotide of any one of embodiments 1-18, wherein the enhancer comprises SEQ ID NO: 6, or a reverse complement thereof.20. The recombinant polynucleotide of any one of embodiments 1-19, wherein the enhancer comprises SEQ ID NO: 7, or a reverse complement thereof.21. The recombinant polynucleotide of any one of embodiments 1-20, wherein the enhancer comprises SEQ ID NO: 8, or a reverse complement thereof.22. The recombinant polynucleotide of any one of embodiments 1-21, wherein the enhancer comprises SEQ ID NO: 9, or a reverse complement thereof.23. The recombinant polynucleotide of any one of embodiments 1-22, wherein the enhancer comprises SEQ ID NO: 10, or a reverse complement thereof.24. The recombinant polynucleotide of any one of embodiments 1-23, wherein the enhancer comprises SEQ ID NO: 11, or a reverse complement thereof.25. The recombinant -221- ^{Docket No. 421688-718021 (718WO1)} polynucleotide of any one of embodiments 1-24, wherein the enhancer comprises SEQ ID NO: 12, or a reverse complement thereof.26. The recombinant polynucleotide of any one of embodiments 1-25, wherein the enhancer comprises SEQ ID NO: 13, or a reverse complement thereof.27. The recombinant polynucleotide of any one of embodiments 1-26, wherein the enhancer comprises SEQ ID NO: 14, or a reverse complement thereof.28. The recombinant polynucleotide of any one of embodiments 1-27, wherein the enhancer comprises SEQ ID NO: 15, or a reverse complement thereof.29. The recombinant polynucleotide of any one of embodiments 1-28, wherein the enhancer comprises SEQ ID NO: 16, or a reverse complement thereof.30. The recombinant polynucleotide of any one of embodiments 1-29, wherein the enhancer comprises SEQ ID NO: 17, or a reverse complement thereof.31. The recombinant polynucleotide of any one of embodiments 1-30, wherein the enhancer comprises SEQ ID NO: 18, or a reverse complement thereof.32. The recombinant polynucleotide of any one of embodiments 1-31, wherein the enhancer comprises SEQ ID NO: 19, or a reverse complement thereof.33. The recombinant polynucleotide of any one of embodiments 1-32, wherein the enhancer comprises SEQ ID NO: 20, or a reverse complement thereof.34. The recombinant polynucleotide of any one of embodiments 1-33, wherein the enhancer comprises two or more of SEQ ID NO: 1 – SEQ ID NO: 20.35. The recombinant polynucleotide of embodiment 34, wherein the enhancer comprises any one of SEQ ID NO: 237 – SEQ ID NO: 266.36. The recombinant polynucleotide of embodiment 34 or embodiment 35, wherein the enhancer comprises SEQ ID NO: 244.37. The recombinant polynucleotide of any one of embodiments 1- 36, wherein the enhancer comprises a duplication of any one of SEQ ID NO: 1 – SEQ ID NO: 20.38. The recombinant polynucleotide of embodiment 37, wherein the enhancer comprises any one of SEQ ID NO: 267 – SEQ ID NO: 286.39. The recombinant polynucleotide of any one of embodiments 1-38, wherein the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, or a YB_TATA promoter.40. The recombinant polynucleotide of any one of embodiments 1-39, wherein the core promoter comprises any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366.41. The recombinant polynucleotide of any one of embodiments 1-40, wherein the core promoter comprises SEQ ID NO: 95.42. The recombinant polynucleotide of any one of embodiments 1-41, further comprising a post-transcriptional regulatory element.43. The recombinant polynucleotide of embodiment 42, wherein the post-transcriptional regulatory element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 287 or SEQ ID NO: 288.44. The recombinant polynucleotide of any one of embodiments 1-43, further comprising a neuron-restrictive silencer element.45. The recombinant polynucleotide of embodiment 44, wherein the neuron-restrictive -222- ^{Docket No. 421688-718021 (718WO1)} silencer element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296.46. The recombinant polynucleotide of any one of embodiments 1-45, further comprising a polyadenylation signal.47. The recombinant polynucleotide of embodiment 46, wherein the polyadenylation signal comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306.48. The recombinant polynucleotide of any one of embodiments 1-47, further comprising a transcriptional pause site.49. The recombinant polynucleotide of embodiment 48, wherein the transcriptional pause site comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 311.50. The recombinant polynucleotide of any one of embodiments 1-49, further comprising a CCCTC-binding factor sequence.51. The recombinant polynucleotide of embodiment 50, wherein the CCCTC-binding factor sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295.52. The recombinant polynucleotide of any one of embodiments 1-51, further comprising a stuffer sequence.53. The recombinant polynucleotide of embodiment 52, wherein the stuffer sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 309.54. The recombinant polynucleotide of any one of embodiments 1-53, comprising a 5’ untranslated region.55. The recombinant polynucleotide of embodiment 54, wherein the 5’ untranslated region comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 310, SEQ ID NO: 353, or SEQ ID NO: 354.56. The recombinant polynucleotide of any one of embodiments 1-55, further comprising a 5’ inverted terminal repeat.57. The recombinant polynucleotide of embodiment 56, wherein the 5’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 307.58. The recombinant polynucleotide of any one of embodiments 1-57, further comprising a 3’ inverted terminal repeat.59. The recombinant polynucleotide of embodiment 58, wherein the 3’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 308.60. The recombinant polynucleotide of any one of embodiments 1- 59, comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 312.61. The recombinant polynucleotide of any one of embodiments 1-60, wherein the payload encodes a protein.62. The recombinant polynucleotide of embodiment 61, wherein the protein is a neuronal protein or an antibody; optionally, wherein the antibody is a therapeutic antibody.63. The recombinant -223- ^{Docket No. 421688-718021 (718WO1)} polynucleotide of embodiment 61 or embodiment 62, wherein the protein is associated with a central nervous system disorder.64. The recombinant polynucleotide of embodiment 63, wherein the central nervous system disorder is a neuronal disorder.65. The recombinant polynucleotide of embodiment 63 or embodiment 64, wherein the central nervous system disorder is a genetic disorder.66. The recombinant polynucleotide of any one of embodiments 61-65, wherein the protein is progranulin or MeCP2.67. The recombinant polynucleotide of embodiment 66, wherein the progranulin encoded by the payload comprises at least 90% sequence identity to SEQ ID NO: 352.68. The recombinant polynucleotide of any one of embodiments 1-60, wherein the payload encodes a therapeutic polynucleotide.69. The recombinant polynucleotide of embodiment 68, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.70. The recombinant polynucleotide of embodiment 68 or embodiment 69, wherein the therapeutic polynucleotide targets a gene.71. The recombinant polynucleotide of embodiment 70, wherein the gene is associated with a central nervous system disorder.72. The recombinant polynucleotide of embodiment 71, wherein the central nervous system disorder is a neuronal disorder.73. The recombinant polynucleotide of embodiment 71 or embodiment 72, wherein the central nervous system disorder is a genetic disorder.74. The recombinant polynucleotide of any one of embodiments 70-73, wherein the gene is GRN or MECP2.75. A plasmid comprising the recombinant polynucleotide of any one of embodiments 1-74.76. The plasmid of embodiment 75, comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 355.77. An engineered viral vector comprising the recombinant polynucleotide of any one of embodiments 1-74 or the plasmid of embodiment 75 or embodiment 76 in a viral vector.78. The engineered viral vector of embodiment 77, wherein the viral vector is an adenoviral vector, an adeno- associated viral vector, or a lentivector.79. The engineered viral vector of embodiment 78, wherein the adeno-associated viral vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV-DJ, AAV-DJ/8, AAV-DJ/9, AAV1/2, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh43, AAV.Rh74, AAV.v66, AAV.Oligo001, AAV.SCH9, AAV.r3.45, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PhP.eB, AAV.PhP.V1, AAV.PHP.B, AAV.PhB.C1, AAV.PhB.C2, AAV.PhB.C3, AAV.PhB.C6, AAV.cy5, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAV.HSC17, AAVhu68, and combinations thereof.80. The engineered viral vector of embodiment 78 or embodiment 79, wherein the adeno-associated viral vector is an AAV5 vector.81. The engineered viral vector of -224- ^{Docket No. 421688-718021 (718WO1)} any one of embodiments 78-80, wherein the adeno-associated viral vector comprises an engineered viral protein (VP) capsid polypeptide.82. The engineered viral vector of embodiment 81, wherein the engineered VP capsid polypeptide comprises at least one substitution in a 581-589 region of the engineered VP capsid polypeptide relative to a wild type VP capsid polypeptide of SEQ ID NO: 313.83. The engineered viral vector of embodiment 82, wherein the 581-589 region comprises a sequence of any one of SEQ ID NO: 320 – SEQ ID NO: 349.84. The engineered viral vector of embodiment 82 or embodiment 83, wherein the 581-589 region comprises a sequence of SEQ ID NO: 321.85. The engineered viral vector of embodiment 82 or embodiment 83, wherein the 581-589 region comprises a sequence of SEQ ID NO: 322.86. The engineered viral vector of embodiment 82 or embodiment 83, wherein the 581-589 region comprises a sequence of SEQ ID NO: 320.87. The engineered viral vector of embodiment 82 or embodiment 83, wherein the 581-589 region comprises a sequence of SEQ ID NO: 334.88. The engineered viral vector of any one of embodiments 82-87, wherein the engineered VP capsid polypeptide comprises a formula of (A)-(X)-(B), wherein (A) is a first polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 318, (X) is the 581-589 region, and (B) is a second polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 319.89. A pharmaceutical composition comprising the recombinant polynucleotide of any one of embodiments 1-74, the plasmid of embodiment 75 or embodiment 76, or the engineered viral vector of any one of embodiments 77-88 and a pharmaceutically acceptable carrier.90. A method of expressing a payload in a target tissue of a subject, the method comprising: administering to the subject the recombinant polynucleotide of any one of embodiments 1-74, the plasmid of embodiment 75 or embodiment 76, the engineered viral vector of any one of embodiments 77-88, or the pharmaceutical composition of embodiment 89 to the subject; and transcribing the payload in the target tissue. 91. The method of embodiment 90, wherein the target tissue is a central nervous system tissue. 92. The method of embodiment 90 or embodiment 91, comprising expressing the payload at a higher level in the target tissue than in a non-target tissue.93. The method of embodiment 92, wherein the non-target tissue is a kidney tissue, a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.94. The method of embodiment 92 or embodiment 93, wherein the target tissue a target cell type, and wherein the non-target tissue comprises a non-target cell type.95. The method of embodiment 94, wherein the target cell type is a neuron or a glial cell.96. The method of embodiment 94 or embodiment 95, wherein the non-target cell type is a renal cell, a retinal cell, a hepatocyte, an epithelial cell, a muscle cell, an erythrocyte, a platelet, a bone marrow cell, an endothelial cell, an epidermal cell, a lymphocyte, an interstitial cell, an -225- ^{Docket No. 421688-718021 (718WO1)} adipocyte, a fibroblast, or combinations thereof.97. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising the recombinant polynucleotide of any one of embodiments 1-74, the plasmid of embodiment 75 or embodiment 76, the engineered viral vector of any one of embodiments 77-88, or the pharmaceutical composition of embodiment 89 to the subject; and expressing a therapeutic sequence encoded by a payload of the recombinant polynucleotide in a target tissue of the subject, thereby treating the disorder.98. The method of embodiment 97, wherein the target tissue is associated with the disorder.99. The method of embodiment 97 or embodiment 98, wherein the disorder is a central nervous system disorder.100. The method of embodiment 99, wherein the central nervous system disorder is a neuronal disorder.101. The method of embodiment 99 or embodiment 100, wherein the central nervous system disorder is a genetic disorder.102. The method of any one of embodiments 99-101, wherein the disorder is Rett syndrome, MECP2 duplication syndrome, frontotemporal dementia, neuronal ceroid lipofuscinosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson’s disease.103. The method of any one of embodiments 99-102, wherein the disorder is any one of the disorders provided in TABLE 3.104. The method of any one of embodiments 99-103, wherein the therapeutic sequence encodes a therapeutic protein.105. The method of embodiment 104, wherein the therapeutic protein is a neuronal protein or an antibody.106. The method of embodiment 104 or embodiment 105, wherein the therapeutic protein is associated with a central nervous system disorder.107. The method of embodiment 106, wherein the central nervous system disorder is a neuronal disorder.108. The method of embodiment 106 or embodiment 104, wherein the central nervous system disorder is a genetic disorder.109. The method of any one of embodiments 104-108, wherein the therapeutic protein is MECP2 or progranulin.110. The method of any one of embodiments 104-109, wherein the therapeutic protein is encoded by a gene provided in TABLE 3.111. The method of any one of embodiments 99-103, wherein the payload encodes a therapeutic polynucleotide.112. The method of embodiment 111, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.113. The method of embodiment 111 or embodiment 112, wherein the therapeutic polynucleotide targets a gene provided in TABLE 3. Further Numbered Embodiments [0487] The following embodiments recite non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated as depending from or relating to every previous or subsequent numbered embodiment, independent of their order as listed.1. A -226- ^{Docket No. 421688-718021 (718WO1)} recombinant polynucleotide according to the present disclosure for use in a method of treating a disorder in a subject in need thereof.2. A recombinant polynucleotide according to the present disclosure for use in a method of treating a disease in a subject in need thereof.3. A recombinant polynucleotide according to the present disclosure for use as a medicament. Further Numbered Embodiments for Liver-Specific Enhancers and Compositions and Methods of Use Thereof [0488] The following embodiments recite non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated as depending from or relating to every previous or subsequent numbered embodiment, independent of their order as listed.1. A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof; and a core promoter.2. The recombinant polynucleotide of embodiment 1, wherein the enhancer comprises a sequence having at least 90% sequence identity to SEQ ID NO: 362, or a reverse complement thereof.3. The recombinant polynucleotide of embodiment 1, wherein the enhancer comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 362, or a reverse complement thereof.4. The recombinant polynucleotide of any one of embodiments 1-3, further comprising a payload, wherein: the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein.5. The recombinant polynucleotide of embodiment 4, wherein the promoter enhances the transcription of the payload in a target tissue.6. The recombinant polynucleotide of embodiment 5, wherein the target tissue is liver tissue.7. The recombinant polynucleotide of embodiment 6, wherein the transcription is enhanced in the liver tissue as compared to a kidney tissue.8. The recombinant polynucleotide of embodiment 6 or embodiment 7, wherein the transcription is enhanced in the liver tissue as compared to a central nervous system tissue, a heart tissue, a lung tissue, or a muscle tissue.9. The recombinant polynucleotide of any one of embodiments 1-8, further comprising a post-transcriptional regulatory element.10. The recombinant polynucleotide of any one of embodiments 1-9, further comprising a polyadenylation signal.11. The recombinant polynucleotide of any one of embodiments 1-10, further comprising a transcriptional pause site.12. The recombinant polynucleotide of any one of embodiments 1-11, wherein the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof.13. The recombinant polynucleotide of -227- ^{Docket No. 421688-718021 (718WO1)} any one of embodiments 1-12, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366.14. The recombinant polynucleotide of any one of embodiments 1-13, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95.15. The recombinant polynucleotide of any one of embodiments 1-14, wherein the core promoter is a sequence of SEQ ID NO: 95.16. The recombinant polynucleotide of any one of embodiments 9-15, wherein the post-transcriptional regulatory element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 287 or SEQ ID NO: 288.17. The recombinant polynucleotide of any one of embodiments 9-16, wherein the post-transcriptional regulatory element comprises a sequence of SEQ ID NO: 288.18. The recombinant polynucleotide of any one of embodiments 9-17, wherein the post-transcriptional regulatory element is downstream of the coding sequence.19. The recombinant polynucleotide of any one of embodiments 10-18, wherein the polyadenylation signal comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306.20. The recombinant polynucleotide of any one of embodiments 10-19, wherein the polyadenylation signal comprises a sequence of SEQ ID NO: 299.21. The recombinant polynucleotide of any one of embodiments 10-20, wherein the polyadenylation signal is downstream of the coding sequence.22. The recombinant polynucleotide of any one of embodiments 11-21, wherein the transcriptional pause site comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 311.23. The recombinant polynucleotide of any one of embodiments 11-22, wherein the transcriptional pause site comprises a sequence of SEQ ID NO: 311.24. The recombinant polynucleotide of any one of embodiments 11-23, wherein the transcriptional pause site is downstream of the coding sequence.25. The recombinant polynucleotide of any one of embodiments 11-24, wherein the transcriptional pause site is downstream of the polyadenylation signal.26. The recombinant polynucleotide of any one of embodiments 11-25, wherein the coding sequence is downstream of the promoter, the post- transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post-transcriptional regulatory element, and the transcriptional pause site is downstream of the post-transcriptional regulatory element.27. The recombinant polynucleotide of any one of embodiments 11-26, wherein the coding sequence is downstream of the promoter, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post-transcriptional regulatory -228- ^{Docket No. 421688-718021 (718WO1)} element, and the transcriptional pause site is downstream of the polyadenylation signal.28. The recombinant polynucleotide of any one of embodiments 1-27, further comprising a CCCTC- binding factor sequence.29. The recombinant polynucleotide of embodiment 28, wherein the CCCTC-binding factor sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295.30. The recombinant polynucleotide of any one of embodiments 1-29, further comprising a stuffer sequence.31. The recombinant polynucleotide of embodiment 30, wherein the stuffer sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 309.32. The recombinant polynucleotide of embodiment 30 or embodiment 31, wherein the stuffer sequence comprises a sequence of SEQ ID NO: 309.33. The recombinant polynucleotide of any one of embodiments 30-32, wherein the stuffer sequence is upstream of the coding sequence.34. The recombinant polynucleotide of any one of embodiments 30-33, wherein the stuffer sequence is upstream of the promoter.35. The recombinant polynucleotide of any one of embodiments 30-34, wherein the stuffer sequence is upstream of the promoter, the coding sequence is downstream of the promoter, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post- transcriptional regulatory element, and the transcriptional pause site is downstream of the polyadenylation signal.36. The recombinant polynucleotide of any one of embodiments 1-35, further comprising a 5’ untranslated region.37. The recombinant polynucleotide of embodiment 36, wherein the 5’ untranslated region comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 310, SEQ ID NO: 353, or SEQ ID NO: 354.38. The recombinant polynucleotide of embodiment 36 or embodiment 37, wherein the 5’ untranslated region comprises a sequence of SEQ ID NO: 310. 39. The recombinant polynucleotide of embodiment 36 or embodiment 37, wherein the 5’ untranslated region comprises a sequence of SEQ ID NO: 353.40. The recombinant polynucleotide of any one of embodiments 36-39, wherein the 5’ untranslated region is upstream of the coding sequence.41. The recombinant polynucleotide of any one of embodiments 36-40, wherein the 5’ untranslated region is downstream of the promoter.42. The recombinant polynucleotide of any one of embodiments 36-41, wherein the stuffer sequence is upstream of the promoter, the 5’ untranslated region is downstream of the promoter, the coding sequence is downstream of the 5’ untranslated region, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post- transcriptional regulatory element, and the transcriptional pause site is downstream of the polyadenylation signal.43. The recombinant polynucleotide of any one of embodiments 1-43, -229- ^{Docket No. 421688-718021 (718WO1)} further comprising a 5’ inverted terminal repeat upstream of the promoter.44. The recombinant polynucleotide of embodiment 43, wherein the 5’ inverted terminal repeat is upstream of the stuffer sequence.45. The recombinant polynucleotide of embodiment 43 or embodiment 44, wherein the 5’ inverted terminal repeat is an AAV55’ inverted terminal repeat, an AAV15’ inverted terminal repeat, an AAV25’ inverted terminal repeat, an AAV95’ inverted terminal repeat, or a PhP.eB 5’ inverted terminal repeat.46. The recombinant polynucleotide of any one of embodiments 43-45, wherein the 5’ inverted terminal repeat is an AAV 5’ inverted terminal repeat.47. The recombinant polynucleotide of embodiment 46, wherein the AAV 5’ inverted terminal repeat is a single stranded AAV 5’ inverted terminal repeat.48. The recombinant polynucleotide of any one of embodiments 43-47, wherein the 5’ inverted terminal repeat is an AAV25’ inverted terminal repeat.49. The recombinant polynucleotide of embodiment 48, wherein the AAV25’ inverted terminal repeat is a single stranded AAV25’ inverted terminal repeat.50. The recombinant polynucleotide of any one of embodiments 43-49, wherein the 5’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 307.51. The recombinant polynucleotide of any one of embodiments 43-50, wherein the 5’ inverted terminal repeat comprises a sequence of SEQ ID NO: 307.52. The recombinant polynucleotide of any one of embodiments 1-51, further comprising a 3’ inverted terminal repeat downstream of the transcriptional pause site.53. The recombinant polynucleotide of embodiment 52, wherein the 3’ inverted terminal repeat is an AAV 3’ inverted terminal repeat.54. The recombinant polynucleotide of embodiment 53, wherein the AAV 3’ inverted terminal repeat is a single stranded AAV 3’ inverted terminal repeat.55. The recombinant polynucleotide of any one of embodiments 52-54, wherein the 3’ inverted terminal repeat is an AAV53’ inverted terminal repeat, an AAV13’ inverted terminal repeat, an AAV23’ inverted terminal repeat, an AAV93’ inverted terminal repeat, or a PhP.eB 3’ inverted terminal repeat.56. The recombinant polynucleotide of any one of embodiments 52-55, wherein the 3’ inverted terminal repeat is an AAV23’ inverted terminal repeat.57. The recombinant polynucleotide of embodiment 56, wherein the AAV23’ inverted terminal repeat is a single stranded AAV23’ inverted terminal repeat.58. The recombinant polynucleotide of any one of embodiments 52-57, wherein the 3’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 308.59. The recombinant polynucleotide of any one of embodiments 52-58, wherein the 3’ inverted terminal repeat comprises a sequence of SEQ ID NO: 308.60. The recombinant polynucleotide of any one of embodiments 52-59, wherein the 5’ inverted terminal repeat is upstream of the stuffer sequence, the stuffer sequence is upstream of the promoter, the 5’ untranslated region is downstream of the -230- ^{Docket No. 421688-718021 (718WO1)} promoter, the coding sequence is downstream of the 5’ untranslated region, the post- transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post-transcriptional regulatory element, the transcriptional pause site is downstream of the polyadenylation signal, and the 3’ inverted terminal repeat downstream of the transcriptional pause site.61. The recombinant polynucleotide of any one of embodiments 4- 60, wherein the payload encodes a protein; optionally, wherein the protein is a therapeutic protein.62. The recombinant polynucleotide of embodiment 61, wherein the protein is a liver protein or an antibody; optionally, wherein the antibody is a therapeutic antibody.63. The recombinant polynucleotide of embodiment 61 or embodiment 62, wherein the protein is associated with a liver disorder.64. The recombinant polynucleotide of embodiment 63, wherein the liver disorder is a genetic disorder.65. The recombinant polynucleotide of any one of embodiments 61-64, wherein the protein is alpha-1 antitrypsin.66. The recombinant polynucleotide of any one of embodiments 4-65, wherein the payload encodes a therapeutic polynucleotide.67. The recombinant polynucleotide of embodiment 66, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.68. The recombinant polynucleotide of embodiment 66 or embodiment 67, wherein the therapeutic polynucleotide targets a gene.69. The recombinant polynucleotide of embodiment 68, wherein the gene is associated with a liver disorder.70. The recombinant polynucleotide of embodiment 68 or embodiment 69, wherein the liver disorder is a genetic disorder.71. The recombinant polynucleotide of any one of embodiments 68-70, wherein the gene is SERPINA1.72. A plasmid comprising the recombinant polynucleotide of any one of embodiments 1-71.73. An engineered viral vector comprising the recombinant polynucleotide of any one of embodiments 1-71.74. The engineered viral vector of embodiment 73, wherein the viral vector is an adenoviral vector, an adeno-associated viral vector, or a lentivector.75. The engineered viral vector of embodiment 74, wherein the adeno- associated viral vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV-DJ, AAV-DJ/8, AAV-DJ/9, AAV1/2, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh43, AAV.Rh74, AAV.v66, AAV.Oligo001, AAV.SCH9, AAV.r3.45, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PhP.eB, AAV.PhP.V1, AAV.PHP.B, AAV.PhB.C1, AAV.PhB.C2, AAV.PhB.C3, AAV.PhB.C6, AAV.cy5, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAV.HSC17, AAVhu68, and combinations thereof.76. The engineered viral vector of embodiment 74 or embodiment 75, wherein the adeno-associated viral vector is an AAV9 vector.77. The engineered viral vector of any one of embodiments 74- -231- ^{Docket No. 421688-718021 (718WO1)} 76, wherein the adeno-associated viral vector comprises an engineered viral protein (VP) capsid polypeptide.78. A pharmaceutical composition comprising the recombinant polynucleotide of any one of embodiments 1-71, the plasmid of embodiment 72, or the engineered viral vector of any one of embodiments 73-77 and a pharmaceutically acceptable carrier.79. A method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide to the target cell or the target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof, and a payload operably linked to the enhancer; and transcribing the payload in the target cell or the target tissue.80. A method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide comprising a promoter to the target cell or the target tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof; and a core promoter; and transcribing the payload in the target cell or the target tissue.81. The method of embodiments 80 or 81, wherein the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof.82. The method of embodiment 80 or embodiment 81, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366.83. The method of embodiment 80 or embodiment 81, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95.84. The method of embodiment 80 or embodiment 81, wherein the core promoter is a sequence of SEQ ID NO: 95.85. The method of any one of embodiments 79-84, wherein the recombinant polynucleotide is the recombinant polynucleotide of any one of embodiments 1-71, or the recombinant polynucleotide is in the plasmid of embodiment 72, or in the engineered viral vector of any one of embodiments 73-77.86. The method of any one of embodiments 79-85, further comprising delivering the recombinant polynucleotide by administering the pharmaceutical composition of embodiment 78 to the subject.87. The method of any one of embodiments 79-86, wherein the target tissue is a liver tissue.88. The method of any one of embodiments 79-87, comprising expressing the payload at a higher level in the target tissue than in a non-target tissue.89. The method of embodiment 88, wherein the non-target tissue is a kidney tissue, a central nervous system tissue, a heart tissue, a lung tissue, or a muscle tissue.90. The method of any one of embodiment 88 or embodiment 89, wherein the target tissue comprises a target cell type, and wherein the non-target tissue comprises a non-target cell type. -232- ^{Docket No. 421688-718021 (718WO1)} 91. The method of any one of embodiments 79-90, wherein the target cell type is a hepatocyte. 92. The method of any one of embodiments 88-91, wherein the non-target cell type is a renal cell, a retinal cell, a neuronal cell, a glial cell, an epithelial cell, a muscle cell, an erythrocyte, a platelet, a bone marrow cell, an endothelial cell, an epidermal cell, a lymphocyte, an interstitial cell, an adipocyte, a fibroblast, or combinations thereof.93. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide to a target cell or a target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof, and a payload operably linked to the enhancer; and expressing a therapeutic sequence encoded by the payload in the target cell or the target tissue of the subject, thereby treating the disorder.94. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide comprising a promoter to a target cell or a target tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof; and a core promoter; and expressing a therapeutic sequence encoded by the payload in the target cell or the target tissue of the subject, thereby treating the disorder.95. The method of embodiment 94, wherein the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof.96. The method of embodiment 94 or embodiment 95, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366.97. The method of embodiment 94 or embodiment 95, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95.98. The method of embodiment 94 or embodiment 95, wherein the core promoter is a sequence of SEQ ID NO: 95.99. The method of any one of embodiments 93-98, wherein the recombinant polynucleotide is the recombinant polynucleotide of any one of embodiments 1-71, or the recombinant polynucleotide is in the plasmid of embodiment 72, or in the engineered viral vector of any one of embodiments 116-123.100. The method of any one of embodiments 93-99, wherein the composition is the pharmaceutical composition of embodiment 124.101. The method of any one of embodiments 93-100, wherein the target tissue is associated with the disorder.102. The method of any one of embodiments 93-101, wherein the disorder is a liver disorder.103. The method of embodiment 102, wherein the liver disorder is a genetic disorder. 104. The method of any one of embodiments 93-103, wherein the disorder is alpha-1 anti-trypsin -233- ^{Docket No. 421688-718021 (718WO1)} deficiency.105. The method of any one of embodiments 93-104, wherein the therapeutic sequence encodes a therapeutic protein.106. The method of embodiment 105, wherein the therapeutic protein is a liver protein or an antibody.107. The method of embodiment 105 or embodiment 106, wherein the therapeutic protein is associated with a liver disorder.108. The method of any one of embodiments 105-107, wherein the therapeutic protein is alpha-1 anti- trypsin.109. The method of any one of embodiments 105-108, wherein the therapeutic protein is encoded by a SERPINA1 gene.110. The method of any one of embodiments 105-109, wherein the payload encodes a therapeutic polynucleotide.111. The method of embodiment 110, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.112. The method of any one of embodiments 94-111, wherein the core promoter is capable of binding to a polymerase. EXAMPLES [0489] The invention is further illustrated by the following non-limiting examples. EXAMPLE 1 Development of an Enhancer/Promoter Library to Screen for Excitatory Neuron-Specific Transcription [0490] This example describes development of an enhancer/promoter (e.g., enhancer/core promoter) library to screen for excitatory neuron-specific transcription. A library of 12,000 enhancers and core promoters was compiled from nucleotide sequences predicted to selectively promote gene transcription in excitatory neurons. Candidate sequences, typically about 170 bases in length, were selected based on single cell sequencing data from fetal cells as well as cell-type specific chromatin accessibility. [0491] Single cell by combinatorial indexing assay for transposase-accessible chromatin with high-throughput sequencing (sci-ATAC-seq) from fetal cells compiled in a publicly available database was used to identify candidate transcription factor binding sequences.5183 candidate regions were identified from regions with sciATAC-seq peak calls in excitatory neurons. The sciATAC-seq peak calls served as markers of chromatin accessibility, predicted to correspond with regions of high transcription. [0492] Additional candidate regions were selected using single cell RNA sequencing data of fetal cells to identify neuronal marker genes. A publicly available database was used to select 2343 candidate regions coinciding with brain active cis-regulatory elements (CCREs) within 100 kilobases of a neuronal marker gene. Likely CCREs included in this database were identified based on data collected using combinations of chromatin immunoprecipitation with massively parallel DNA (ChIP-seq), DNase I hypersensitive sites sequencing (DNase-seq), and -234- ^{Docket No. 421688-718021 (718WO1)} chromosome conformation capture (HiC). Another public database was used to further identify candidate regions coinciding with enhancers specific to midbrain or forebrain gene expression. [0493] FIG.1 illustrates a profile of a candidate enhancer located within an intron for the gene opioid-binding protein/cell adhesion molecule (OPCML). Parameters of the region that were analyzed include single cell chromatin accessibility in nervous tissue including excitatory neurons (Row 1), cerebellar astrocytes (Row 2), cerebellar vascular endothelial cells (Row 3), cerebellar astrocytes (Row 4), and LUHMES-derived neurons (Row 7 and Row 8). Chromatin accessibility in nervous tissue was compared to chromatin accessibility in liver hepatocytes (Row 5) and in liver myeloid cells (Row 6). The candidate region was also narrowed based on sequence conservation across vertebrates (Row 9) and H3K27ac epigenetic modifications in brain tissue derived from a human donor (Row 10). The candidate region was narrowed (Row 11) and a 170 base region was selected (Row 12) for inclusion in the library. [0494] The neuronal marker gene (opioid-binding protein/cell adhesion molecule (OPCML)) located near the candidate enhancer also showed strong expression, in transcripts per million (TPM), in brain tissues, including amygdala, anterior cingulate cortex, caudate (basal ganglia), cerebellar hemisphere, cerebellum, cortex, frontal cortex, hippocampus, hypothalamus, nucleus accumbens (basal ganglia), putamen (basal ganglia), cervical C1 spinal cord, and substantia nigra, as shown in FIG.2. [0495] Each of the identified candidate regions were narrowed to a 170 base nucleotide sequence using sci-ATAC-seq data. ATAC-seq data tracks covering the candidate region were tiled to identify the 170 base nucleotide sequence covering the region with the highest ATAC-seq signal. The region with the highest signal was predicted to have the highest neuron-specific transcription enhancement. [0496] Additionally, 294 promoter regions of the neuronal marker genes identified using single cell RNA sequencing were included in the enhancer/promoter (e.g., enhancer/core promoter) library in both sense and anti-sense orientations. One hundred reference sequences not anticipated to promote neuron-specific gene transcription were also included in the library for cross-comparison between screens. [0497] The 12,000-member library was generated having a polynucleotide encoding a GFP reporter payload, a YB_TATA core promoter, and the identified enhancers. This library was used for screening in neurons using a massively parallel reporter assay, as shown in FIG.3. Briefly, candidate sequences were synthesized, and PCR was performed to add a 15 base random barcode sequence and Gibson homology arms to each candidate or reference member of the -235- ^{Docket No. 421688-718021 (718WO1)} library. The resulting constructs were cloned into carrier plasmids. Next generation sequencing was used to associate each candidate sequence with its corresponding random barcode sequence. Reporter constructs contained and were already associated with random barcode sequences, so PCR was performed on each of the reporter constructs to add Gibson homology arms. Candidate constructs and control constructs were cloned into either a lentiviral transfer plasmid or an AAV plasmid for high-throughput screening. High-throughput screening was conducted in a variety of cell lines and mouse tissues, a truncated GFP reporter gene transcript abundance was assessed, and promoter activity was determined by NGS of matched barcodes. EXAMPLE 2 Screening of a CNS Enhancer/Promoter Library to Identify CNS-Specific Transcriptional Enhancers [0498] This example describes screening of a CNS enhancer/promoter (e.g., enhancer/core promoter) library to identify transcriptional enhancers that enhance transcriptional activity in CNS tissue. An enhancer/promoter (e.g., enhancer/core promoter) library was compiled as described in EXAMPLE 1. Candidate sequences were screened in a massively parallel reporter assay. Enrichment of barcoded mRNA was compared to DNA input to assess the activity of each promoter in the library. High throughput screening was performed in HepG2 liver cells, H4 neuroglioma cells, K562 lymphoblasts, Lund human mesencephalic (LUHMES) cells, and in mouse primary neuronal cells. Screening was also conducted in vivo in brain, gastrocnemius, heart, kidney, liver, and lung tissues from collected from wild type C57BL/6 mice. Cells were harvested, and promoter activity was determined by next generation sequencing of matched DNA and RNA barcodes. Activity was expressed as log RNA / DNA to normalize to library DNA levels. As shown in FIG.4 – FIG.7, candidate sequences were selected for increased expression in neuronal cells or tissues relative to liver cells or tissues. [0499] Candidate CNS-enhancers, shown as black points in FIG.4A – FIG.4C, exhibited increased transcriptional activity in mouse primary neurons as compared to a HepG2 liver cell line, as shown in FIG.4A, in in Lund human mesencephalic (LUHMES) cells as compared to a HepG2 liver cell line, as show in FIG.4B, and in mouse brain tissue as compared to mouse liver tissue, as shown in FIG.4C. The identified CNS-enhancer candidates also exhibited consistently higher transcriptional activity in brain tissue across five replicate mice, as shown in FIG.5. Additionally, the CNS-enhancer candidates exhibited higher transcriptional activity in mouse brain tissues as compared to leg muscle (gastrocnemius), heart, kidney, liver, and lung tissues, as shown in FIG.6 and FIG.30. The CNS-enhancer candidates had exhibited higher transcriptional activity in LUHMES cells as compared to HepG2 liver cells and had similar -236- ^{Docket No. 421688-718021 (718WO1)} enrichment in LUHMES cells as compared to other neuronal cell lines, including H4, K562, and mouse primary neurons, as shown in FIG.7A. Similarly, CNS-enhancer candidates exhibited higher transcriptional activity in mouse primary neurons when compared to HepG2 liver cells and had similar enrichment in mouse primary neurons as compared to other neuronal cell lines, including H4, K562, and LUHMES cells, as shown in FIG.7B. Selected CNS-enhancer candidates (“novel CNS promoters”) exhibited increased expression of a GRN payload in mouse primary neurons (FIG.31A) compared to GRN payload expression in liver-like HepG2 cells (FIG.31B). As shown in FIG.31A and FIG.31B, payload expression under control of the selected CNS-enhancer candidates was higher in mouse primary neurons and lower in HepG2 cells than payload expression under control of a constitutive promoter. [0500] The transcriptional activity of the enhancer/promoter (e.g., enhancer/core promoter) library was then compared between CNS cells and tissues including LUHMES cells, mouse primary neurons, and mouse brain tissue to identify enhancers with CNS-specific activity. Transcriptional activity in CNS cells and tissues was compared to non-CNS cells and tissues including HepG2 cells, K562 cells, and mouse liver tissue. Expression constructs were delivered either as pGL4 plasmids (LUHMES, HepG2, and K562 cells) or by AAV viral delivery (mouse primary neurons, mouse tissues, and HepG2 cells). Candidate CNS-enhancers identified in LUHMES cells, represented by the indicated points, showed enhanced activity in mouse brain tissue as compared to mouse liver tissue, as shown in FIG.8A. Candidate CNS-enhancers identified in LUHMES cells, represented by the indicated points, showed enhanced activity in LUHMES cells as compared to HepG2 cells, as shown in FIG.8B. Candidate CNS-enhancers identified in LUHMES cells, represented by the indicated points, showed enhanced activity in mouse primary neuron cells as compared to mouse liver tissue, as shown in FIG.8C. The activity of the enhancer/promoter (e.g., enhancer/core promoter) library was also compared across CNS cell and tissue models. A comparison of CNS-enhancer transcriptional activity in mouse brain tissue and mouse primary neurons is shown in FIG.9A. A comparison of CNS- enhancer transcriptional activity in LUHMES cells and mouse brain tissue is shown in FIG.9B. A comparison of CNS-enhancer transcriptional activity in mouse primary neurons and LUHMES cells is shown in FIG.9C. EXAMPLE 3 Selection of CNS-Enhancer Candidates [0501] This example describes the selection of CNS-enhancer candidates from the enhancer/promoter (e.g., enhancer/core promoter) library screen described in EXAMPLE 1. Candidates were selected based on parameters including: 1) activity in LUHMES cells versus -237- ^{Docket No. 421688-718021 (718WO1)} activity in HepG2 cells; 2) activity in mouse primary neurons versus activity in HepG2 cells; and 3) activity in mouse brain tissue versus activity in mouse liver, heart, kidney, gastrocnemius (“gastro”), and lung tissues. The activities of CNS-enhancer candidates of SEQ ID NO: 1 – SEQ ID NO: 20 in LUHMES cells, mouse primary neurons (MPN), and mouse brain tissue are provided in TABLE 10. Expression constructs containing each of the candidate enhancers were delivered as pGL4 plasmids (LUHMES, HepG2, and K562 cells) or by AAV viral delivery (mouse primary neurons, mouse tissues, and HepG2 cells) to measure payload expression driven by the candidate enhancers. Transcriptional activity was expressed as the log of the fold change in expression (logFC). Fold change in activity LUHMES cells, mouse primary neurons, and mouse brain tissue was determined relative to activity in HepG2 cells. Adjusted p-value “adj.P.Val” were determined for the fold change in activity for each cell or tissue type. TABLE 10 – Transcriptional Activity of CNS-Enhancers SEQ ID NO: logFC adj.P.Val logFC adj.P.Val logFC (Mouse adj.P.Val (LUHMES) (LUHMES) (MPN) (MPN) brain) (Mouse brain) SEQ ID NO: 1 0.61 1.2E-01 2.55 4.3E-07 6.21 6.4E-19 SEQ ID NO: 2 -0.52 1.1E-01 3.24 2.1E-09 5.57 7.7E-20 SEQ ID NO: 3 2.12 1.1E-04 1.48 2.6E-04 5.53 2.5E-13 SEQ ID NO: 4 6.14 2.3E-11 4.83 1.2E-11 5.44 3.6E-31 SEQ ID NO: 5 0.80 2.5E-05 4.56 4.6E-15 5.20 4.3E-32 SEQ ID NO: 6 1.10 1.1E-02 2.05 6.8E-06 6.20 3.3E-15 SEQ ID NO: 7 -0.63 1.6E-01 2.34 5.2E-06 6.03 1.3E-17 SEQ ID NO: 8 -0.89 3.0E-02 2.74 2.0E-07 5.94 1.3E-16 SEQ ID NO: 9 1.51 8.3E-04 2.39 5.6E-07 5.80 4.8E-15 SEQ ID NO: 10 1.06 1.2E-02 3.46 1.2E-08 5.44 3.8E-25 SEQ ID NO: 11 -1.81 6.0E-05 2.67 3.1E-08 5.41 9.6E-14 SEQ ID NO: 12 0.51 4.4E-01 3.46 5.5E-09 5.22 1.0E-28 SEQ ID NO: 13 2.43 9.6E-06 2.80 6.8E-08 5.21 2.0E-11 SEQ ID NO: 14 -0.01 9.6E-01 4.84 3.0E-13 4.91 6.0E-28 SEQ ID NO: 15 0.56 3.3E-03 4.08 1.9E-13 4.87 7.7E-24 SEQ ID NO: 16 0.43 3.5E-03 3.38 1.0E-13 4.77 1.2E-28 SEQ ID NO: 17 2.06 3.3E-04 1.53 4.6E-04 4.66 1.6E-11 SEQ ID NO: 18 0.24 1.2E-01 3.91 1.0E-13 4.43 7.7E-24 SEQ ID NO: 19 0.70 3.0E-04 4.03 1.0E-13 4.40 6.8E-24 SEQ ID NO: 20 0.30 3.3E-02 3.80 5.3E-14 4.22 5.9E-25 [0502] Each of the CNS-enhancer candidates of SEQ ID NO: 1 – SEQ ID NO: 20 exhibited higher transcriptional activity, expressed as a log ratio (“lr”), in mouse brain tissue than in -238- ^{Docket No. 421688-718021 (718WO1)} mouse heart, kidney, liver, lung, or muscle tissue, as shown in FIG.10 – FIG.29, respectively. FIG.10 – FIG.29 provide violin plots of the transcriptional activity with underlying boxplots that represent the ratio of RNA to DNA for individual redundant barcodes paired with the enhancer in the screen outlined in FIG.3. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 1 is shown in FIG.10. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 2 is shown in FIG.11. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 3 is shown in FIG.12. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 4 is shown in FIG.13. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 5 is shown in FIG.14. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 6 is shown in FIG.15. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 7 is shown in FIG.16. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 8 is shown in FIG.17. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 9 is shown in FIG.18. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 10 is shown in FIG.19. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 11 is shown in FIG.20. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 12 is shown in FIG.21. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 13 is shown in FIG.22. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 14 is shown in FIG. 23. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 15 is shown in FIG.24. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 16 is shown in FIG.25. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 17 is shown in FIG.26. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 18 is shown in FIG.27. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 19 is shown in FIG. 28. The activity in mouse brain, heart, kidney, liver, lung, and muscle tissue of SEQ ID NO: 20 is shown in FIG.29. EXAMPLE 4 Transcriptional Activity and Neuronal Cell Specificity of CNS-Enhancer Candidates [0503] This example describes the transcriptional activity and neuronal cell specificity of CNS- enhancer candidates. CNS-enhancer candidates of SEQ ID NO: 1 – SEQ ID NO: 20 identified in EXAMPLE 3 were further tested for transcriptional activity and specificity. Dual expression cassettes were generated for each of the twenty CNS-enhancer candidates (SEQ ID NO: 1 – -239- ^{Docket No. 421688-718021 (718WO1)} SEQ ID NO: 20). Each dual expression cassette, as illustrated in FIG.32, included a first expression construct encoding a human progranulin (“hPGRN”) under control of the CNS- enhancer candidate (selected from SEQ ID NO: 1 – SEQ ID NO: 20) and a minP variant core promoter of SEQ ID NO: 95 (“Enhancer + minP”) with a WPRE3 regulatory element and a polyA sequence, and a second expression construct encoding luciferase (“s_nLuciferase”) under control of a CMV promoter with a polyA sequence. The two expression constructs are separated by an insulator. Control dual expression cassettes were also generated with either an RSV promoter (“RSV”), a human synapsin promoter (“hSyn”), or a scrambled promoter (“scrambled”) in place of a CNS-enhancer candidate. Mouse primary neurons (MPN) and human induced pluripotent stem cell derived neurons (iPSC) were transduced with AAV1 virions containing a dual expression cassette with one of the CNS-enhancer candidates (SEQ ID NO: 1 – SEQ ID NO: 20). HepG2 cells were transfected with plasmids encoding the dual expression cassette. Mouse primary neuron (MPN) and iPSC transduction and HepG2 transfection were repeated in different cell populations for dual expression cassettes containing each of the twenty CNS-enhancer candidates of SEQ ID NO: 1 – SEQ ID NO: 20, the RSV promoter, the human synapsin promoter, and the scrambled promoter. Expression levels were compared seven days after transduction. Cells that were not transduced (“no virus”) were used as a negative control. [0504] Enhancer activity in each cell type was determined by normalizing expression levels of the progranulin under transcriptional control of the CNS-enhancer candidate or control promoter to expression levels of luciferase expressed from the same expression cassette. Neuronal ^{specificity in IPSCs was determined as follows:} ^{( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^)} _{⁄ ( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^)} _{( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^2)⁄ ( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^2)} ^{[0505] Neuronal specificity in MPNs was determined as follows:} ^{( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^)} _{⁄ ( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^)} _{( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^2)⁄ ( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^2)} [0506] Neuronal specificity of each of SEQ ID NO: 1 – SEQ ID NO: 20 was compared to a non- specific RSV promoter, a neuron-specific human synapsin promoter, and an inactive scrambled promoter in human induced pluripotent stem cell derived neurons compared to HepG2 and in mouse primary neurons compared to HepG2. FIG.33A shows neuronal specificity of CNS- enhancer candidates in human induced pluripotent stem cell derived neurons (iPSC; solid line -240- ^{Docket No. 421688-718021 (718WO1)} bars) and neuronal specificity of CNS-enhancer candidates in mouse primary neurons (MPN; dashed line bars). [0507] Activity of each of SEQ ID NO: 1 – SEQ ID NO: 20 was compared to the RSV promoter, the human synapsin promoter, and the scrambled promoter in human induced pluripotent stem cell derived neurons and in mouse primary neurons. FIG.33B shows activity of CNS-enhancer candidates in human induced pluripotent stem cell derived neurons (iPSC; solid line bars) and activity of CNS-enhancer candidates in mouse primary neurons (MPN; dashed line bars). [0508] Based on the specificity and activity data, CNS-enhancers of SEQ ID NO: 13, SEQ ID NO: 4, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 19, and SEQ ID NO: 20 were selected for further study. EXAMPLE 5 Development of an Enhancer/Promoter Library to Screen for Liver-Specific Transcription [0509] This example describes development of an enhancer/promoter (e.g., enhancer/core promoter) library to screen for liver-specific transcription. A library of enhancer sequences and core promoter sequences was compiled from nucleotide sequences predicted to selectively promote tissue-specific gene transcription. Candidate sequences, typically about 170 bases in length, were selected based on single sequencing data from fetal cells as well as cell-type specific chromatin accessibility. [0510] Single cell by combinatorial indexing assay for transposase-accessible chromatin with high-throughput sequencing (sci-ATAC-seq) from fetal cells compiled in a publicly available database was used to identify candidate transcription factor binding sequences. Candidate regions were identified from regions with sciATAC-seq peaks in hepatocytes. The sciATAC-seq peaks served as markers of chromatin accessibility, predicted to correspond with regions of high transcription. [0511] Additional candidate regions were selected using single cell RNA sequencing data of fetal cells to identify hepatic genes. A publicly available database was used to select candidate regions coinciding with hepatic active cis-regulatory elements (CCREs) within 100 kilobases of a hepatic marker gene. Likely CCREs included in this database were identified based on data collected using combinations of chromatin immunoprecipitation with massively parallel DNA (ChIP-seq), DNase I hypersensitive sites sequencing (DNase-seq), and chromosome conformation capture (HiC). Another public database was used to further identify candidate regions coinciding with enhancers specific to liver gene expression. -241- ^{Docket No. 421688-718021 (718WO1)} EXAMPLE 6 Screening of a Liver Enhancer/Promoter Library to Identify Liver-Specific Transcriptional Enhancers [0512] This example describes screening of a liver enhancer/promoter (e.g., enhancer/core promoter) library to identify transcriptional enhancers that enhance transcriptional activity in liver tissue. An enhancer/promoter (e.g., enhancer/core promoter) library was compiled as described in EXAMPLE 5. Candidate sequences were screened in a massively parallel reporter assay as shown in FIG.3. Briefly, candidate sequences were synthesized, and PCR was performed to add a 15 base random barcode sequence and Gibson homology arms to each candidate or reference member of the library. The resulting constructs were cloned into carrier plasmids. Next generation sequencing was used to associate each candidate sequence with its corresponding random barcode sequence. Reporter constructs contained and were already associated with random barcode sequences, so PCR was performed on each of the reporter constructs to add Gibson homology arms. Candidate constructs and control constructs were cloned into either a lentiviral transfer plasmid or an AAV plasmid for high-throughput screening. High-throughput screening was conducted, GRN transcript abundance is assessed, and promoter activity was determined by NGS of matched barcodes. [0513] Enrichment of barcoded mRNA was compared to DNA input to assess the activity of each promoter in the library. High throughput screening was performed in HepG2 liver cells, H4 neuroglioma cells, K562 lymphoblasts, Lund human mesencephalic (LUHMES) cells, and in mouse primary neuronal cells. Screening was also conducted in vivo in brain, gastrocnemius, heart, kidney, liver, and lung tissues from collected from wild type C57BL/6 mice. Cells were harvested, and promoter activity was determined by next generation sequencing of matched DNA and RNA barcodes. Activity was expressed as log RNA / DNA to normalize to DNA transfection levels. The transcriptional activity, shown in FIG.30, of candidate promoters was measured in mouse brain, heart, liver, and lung tissues. Liver-specific candidates were identified that exhibited higher transcriptional activity in liver tissue than in heart, brain, or lung tissues, as shown in FIG.30. EXAMPLE 7 Further Analysis of Specific Transcription Activation by CNS Enhancers and Liver Enhancers [0514] Specific transcription activation by CNS enhancer sequences and liver enhancer sequences was determined by comparing transcriptional activation of a core promoter when paired with an active CNS-specific enhancer (SEQ ID NO: 360) or an active liver-specific -242- ^{Docket No. 421688-718021 (718WO1)} enhancer (SEQ ID NO: 362) relative to transcriptional activation when paired with an inactive enhancer (SEQ ID NO: 361). [0515] Core promoter expression constructs were generated by piecing together an enhancer (e.g., any one of SEQ ID NO: 362, SEQ ID NO: 360, or SEQ ID NO: 361) and a core promoter (e.g., any one of SEQ ID NO: 95, SEQ ID NO: 107, and SEQ ID NO: 363 – SEQ ID NO: 366), such that the construct sequence included, from 5’ to 3’, the enhancer followed by the core promoter. Select enhancer + core promoter sequences that were assayed are provided in TABLE 11. TABLE 11 – Assayed Enhancer/Core Promoter Sequences Enhancer/ Core Enhancer/Core Promoter Sequence Enhancer ^Core Promoter _Promoter SEQ ID TCTTACCAGTGTGTGGCCTTGGGTCCTGGAAAAGT SEQ ID SEQ ID NO: 379 CCTTCATTTAGAGCAGAAACCAAAGCTTCAGCTTT NO: 362 NO: 107 GCAGCCCAGAACCTTCAGCAAATATTTGCTATTCC AAAGTATGATCCCCTGTGGGACGGTTACTGATTAA CATCCTGCTTGTGATGGTGGAGTTTCTGGAGGGGT ATAAAAGGCGGGGTGGAAGGCGATTTCAGTCTTG SEQ ID TCTTACCAGTGTGTGGCCTTGGGTCCTGGAAAAGT SEQ ID SEQ ID NO: 380 CCTTCATTTAGAGCAGAAACCAAAGCTTCAGCTTT NO: 362 NO: 363 GCAGCCCAGAACCTTCAGCAAATATTTGCTATTCC AAAGTATGATCCCCTGTGGGACGGTTACTGATTAA CATCCTGCTTGTGATGGTGGAGTTTCTGGAGGGGT ATAAAAAACGTCGGCGCGGGTGATTACTGTCAGTC TTTTGG SEQ ID TCTTACCAGTGTGTGGCCTTGGGTCCTGGAAAAGT SEQ ID SEQ ID NO: 381 CCTTCATTTAGAGCAGAAACCAAAGCTTCAGCTTT NO: 362 NO: 364 GCAGCCCAGAACCTTCAGCAAATATTTGCTATTCC AAAGTATGATCCCCTGTGGGACGGTTACTGATTAA CATCCTGCTTGTGATGGTGGAGTTTCTGGAGGGGT ATAAAAGGCTGGCGGGGACAGATAAGATCAGTCTT TTGG SEQ ID TCTTACCAGTGTGTGGCCTTGGGTCCTGGAAAAGT SEQ ID SEQ ID NO: 382 CCTTCATTTAGAGCAGAAACCAAAGCTTCAGCTTT NO: 362 NO: 365 GCAGCCCAGAACCTTCAGCAAATATTTGCTATTCC AAAGTATGATCCCCTGTGGGACGGTTACTGATTAA CATCCTGCTTGTGATGGTGGAGTTTCTGGAGGGGT ATAAAAGCCGGGGAGGAACAGATAAGATCAGTCT GTTGG SEQ ID TCTTACCAGTGTGTGGCCTTGGGTCCTGGAAAAGT SEQ ID SEQ ID NO: 383 CCTTCATTTAGAGCAGAAACCAAAGCTTCAGCTTT NO: 362 NO: 95 GCAGCCCAGAACCTTCAGCAAATATTTGCTATTCC AAAGTATGATCCCCTGTGGGACGGTTACTGATTAA CATCCTGCTTGTGATGGTGGAGTTTCTGGATAGAG -243- ^{Docket No. 421688-718021 (718WO1)} Enhancer/ Core Enhancer/Core Promoter Sequence Enhancer ^Core Promoter _Promoter GGTATATAAAGGAAGCTCGACTTCCAGCTTGGCAT TCCGG SEQ ID TCTTACCAGTGTGTGGCCTTGGGTCCTGGAAAAGT SEQ ID SEQ ID NO: 384 CCTTCATTTAGAGCAGAAACCAAAGCTTCAGCTTT NO: 362 NO: 366 GCAGCCCAGAACCTTCAGCAAATATTTGCTATTCC AAAGTATGATCCCCTGTGGGACGGTTACTGATTAA CATCCTGCTTGTGATGGTGGAGTTTCTGGATAGAT GGTATATAAGGGAGGCTCGACATCCAGTTGGGCAA TCCGG SEQ ID TGGGGGTGGCTTTCTGAGGTTTCCATTGGGGGGCA SEQ ID SEQ ID NO: 367 GCCAGAGGCAGAGGGCAGGGGCTGGGACTGCCTA NO: 360 NO: 107 TGCATGCATGTTTGTGTGTGTTTGTGTGTGCGCAGG CGTGTTGTTGGCACGGACGTGACTCTGCATTATCC GGGCCCGTAATGAGTCCTCATTGCAATGGGGGGGT ATAAAAGGCGGGGTGGAAGGCGATTTCAGTCTTG SEQ ID TGGGGGTGGCTTTCTGAGGTTTCCATTGGGGGGCA SEQ ID SEQ ID NO: 368 GCCAGAGGCAGAGGGCAGGGGCTGGGACTGCCTA NO: 360 NO: 363 TGCATGCATGTTTGTGTGTGTTTGTGTGTGCGCAGG CGTGTTGTTGGCACGGACGTGACTCTGCATTATCC GGGCCCGTAATGAGTCCTCATTGCAATGGGGGGGT ATAAAAAACGTCGGCGCGGGTGATTACTGTCAGTC TTTTGG SEQ ID TGGGGGTGGCTTTCTGAGGTTTCCATTGGGGGGCA SEQ ID SEQ ID NO: 369 GCCAGAGGCAGAGGGCAGGGGCTGGGACTGCCTA NO: 360 NO: 364 TGCATGCATGTTTGTGTGTGTTTGTGTGTGCGCAGG CGTGTTGTTGGCACGGACGTGACTCTGCATTATCC GGGCCCGTAATGAGTCCTCATTGCAATGGGGGGGT ATAAAAGGCTGGCGGGGACAGATAAGATCAGTCTT TTGG SEQ ID TGGGGGTGGCTTTCTGAGGTTTCCATTGGGGGGCA SEQ ID SEQ ID NO: 370 GCCAGAGGCAGAGGGCAGGGGCTGGGACTGCCTA NO: 360 NO: 365 TGCATGCATGTTTGTGTGTGTTTGTGTGTGCGCAGG CGTGTTGTTGGCACGGACGTGACTCTGCATTATCC GGGCCCGTAATGAGTCCTCATTGCAATGGGGGGGT ATAAAAGCCGGGGAGGAACAGATAAGATCAGTCT GTTGG SEQ ID TGGGGGTGGCTTTCTGAGGTTTCCATTGGGGGGCA SEQ ID SEQ ID NO: 371 GCCAGAGGCAGAGGGCAGGGGCTGGGACTGCCTA NO: 360 NO: 95 TGCATGCATGTTTGTGTGTGTTTGTGTGTGCGCAGG CGTGTTGTTGGCACGGACGTGACTCTGCATTATCC GGGCCCGTAATGAGTCCTCATTGCAATGGGTAGAG GGTATATAAAGGAAGCTCGACTTCCAGCTTGGCAT TCCGG -244- ^{Docket No. 421688-718021 (718WO1)} Enhancer/ Core Enhancer/Core Promoter Sequence Enhancer ^Core Promoter _Promoter SEQ ID TGGGGGTGGCTTTCTGAGGTTTCCATTGGGGGGCA SEQ ID SEQ ID NO: 372 GCCAGAGGCAGAGGGCAGGGGCTGGGACTGCCTA NO: 360 NO: 366 TGCATGCATGTTTGTGTGTGTTTGTGTGTGCGCAGG CGTGTTGTTGGCACGGACGTGACTCTGCATTATCC GGGCCCGTAATGAGTCCTCATTGCAATGGGTAGAT GGTATATAAGGGAGGCTCGACATCCAGTTGGGCAA TCCGG SEQ ID GCCACTGCACTCCGTGCTGGGCAACTGAGTGAGAC SEQ ID SEQ ID NO: 373 CCCATCTCAAAAAACTCAAAAAAGAGTTAAAATAA NO: 361 NO: 107 ATCACTGTCTATTGTGCCAAAGAGCTGTTGAAGTC ATCATTCTTAGAAGAATAGACAGATGGTATTTCAA GGCTTGGGGTATAAAAGGCGGGGTGGAAGGCGAT TTCAGTCTTG SEQ ID GCCACTGCACTCCGTGCTGGGCAACTGAGTGAGAC SEQ ID SEQ ID NO: 374 CCCATCTCAAAAAACTCAAAAAAGAGTTAAAATAA NO: 361 NO: 363 ATCACTGTCTATTGTGCCAAAGAGCTGTTGAAGTC ATCATTCTTAGAAGAATAGACAGATGGTATTTCAA GGCTTGGGGTATAAAAAACGTCGGCGCGGGTGATT ACTGTCAGTCTTTTGG SEQ ID GCCACTGCACTCCGTGCTGGGCAACTGAGTGAGAC SEQ ID SEQ ID NO: 375 CCCATCTCAAAAAACTCAAAAAAGAGTTAAAATAA NO: 361 NO: 364 ATCACTGTCTATTGTGCCAAAGAGCTGTTGAAGTC ATCATTCTTAGAAGAATAGACAGATGGTATTTCAA GGCTTGGGGTATAAAAGGCTGGCGGGGACAGATA AGATCAGTCTTTTGG SEQ ID GCCACTGCACTCCGTGCTGGGCAACTGAGTGAGAC SEQ ID SEQ ID NO: 376 CCCATCTCAAAAAACTCAAAAAAGAGTTAAAATAA NO: 361 NO: 365 ATCACTGTCTATTGTGCCAAAGAGCTGTTGAAGTC ATCATTCTTAGAAGAATAGACAGATGGTATTTCAA GGCTTGGGGTATAAAAGCCGGGGAGGAACAGATA AGATCAGTCTGTTGG SEQ ID GCCACTGCACTCCGTGCTGGGCAACTGAGTGAGAC SEQ ID SEQ ID NO: 377 CCCATCTCAAAAAACTCAAAAAAGAGTTAAAATAA NO: 361 NO: 95 ATCACTGTCTATTGTGCCAAAGAGCTGTTGAAGTC ATCATTCTTAGAAGAATAGACAGATGGTATTTCAA GGCTTTAGAGGGTATATAAAGGAAGCTCGACTTCC AGCTTGGCATTCCGG SEQ ID GCCACTGCACTCCGTGCTGGGCAACTGAGTGAGAC SEQ ID SEQ ID NO: 378 CCCATCTCAAAAAACTCAAAAAAGAGTTAAAATAA NO: 361 NO: 366 ATCACTGTCTATTGTGCCAAAGAGCTGTTGAAGTC ATCATTCTTAGAAGAATAGACAGATGGTATTTCAA GGCTTTAGATGGTATATAAGGGAGGCTCGACATCC AGTTGGGCAATCCGG -245- ^{Docket No. 421688-718021 (718WO1)} [0516] Transcriptional activation for each of the enhancer/core promoter constructs was measured in H4 cells (CNS-cell type) and HepG2 cells (liver cell-type), and fold activation (fold-change) was determined by measuring transcriptional activation when paired with a tissue- specific enhancer (e.g., CNS-specific enhancer (e.g., SEQ ID NO: 360) or liver-specific enhancer (SEQ ID NO: 362)) divided by transcriptional activation when paired with an inactive enhancer (e.g., SEQ ID NO: 361) in each cell-type. [0517] The enhancer/core promoter constructs provided in TABLE 11, were each introduced into a dual reporter plasmid with an enhancer/core promoter-driven GFP-reporter and a constitutive promoter-driven mCherry-reporter. The plasmids were introduced into HepG2 cells using lipofection and into H4 cells using nucleofection. The cells were then incubated for 48 hours and the fluorescence of each of the reporters was measured by flow cytometry. [0518] As shown in FIG.37A, in H4 cells the enhancer/core promoter constructs comprising the CNS-specific enhancer i.e., the CNS-enhancer (SEQ ID NO: 360) and the promoters SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, and SEQ ID NO: 107 all showed a greater ratio of GFP-reporter mean fluorescence intensity over mCherry- reporter mean fluorescence intensity (“GFP gMFI / mCherry gMFI”) than the enhancer/core promoter constructs with a liver-specific enhancer (SEQ ID NO: 362) or the inactive enhancer (SEQ ID NO: 361). As further shown in FIG.37A, fold activation of transcription was higher when the core promoters were paired with H4 cell type-specific enhancers in H4 cells than when paired with HepG2 cell-type specific enhancers in H4 cells, suggesting that the core promoters selectively initiated transcription in the presence of CNS-specific enhancers specific to the given cell type (i.e., CNS cell-type) while exhibiting low transcriptional activation in the presence of enhancers specific for other cell types. As shown in FIG.37B, fold activation of transcription was lower with the enhancer/core promoter constructs comprising the CNS-specific enhancer (SEQ ID NO: 360) when paired with a core promoter of SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, or SEQ ID NO: 107 than the expression constructs comprising a liver-specific enhancer (HepG2 cell type-specific enhancer of SEQ ID NO: 362) paired with the same core promoters in HepG2 cells. These observations suggest that the CNS-specific enhancer (SEQ ID NO: 360) selectively enhanced transcription in CNS cell types while exhibiting lower transcriptional enhancement in the presence of liver cell types. [0519] As shown in FIG.38A, in H4 cells the enhancer/core promoter constructs comprising the H4-enhancer (SEQ ID NO: 360, “active enhancer”) when paired with a core promoter of SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, or SEQ ID NO: 107 all showed increased transcriptional activity of the active enhancer (the H4 -246- ^{Docket No. 421688-718021 (718WO1)} enhancer of SEQ ID NO: 360) when paired with a core promoter over the transcriptional activity of the inactive enhancer (SEQ ID NO: 361) when paired with a core promoter, indicated by a fold change over 1.0. Further in many of the constructs, the fold change was greater than 1.5- fold. The greatest fold change (around 1.7-fold) was seen in SEQ ID NO: 365 and SEQ ID NO: 366. [0520] As shown in FIG.37B, in HepG2 cells the enhancer/core promoter constructs comprising the liver-specific enhancer (the HepG2-enhancer (SEQ ID NO: 362)) when paired with a core promoter of SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, and SEQ ID NO: 107 all showed a greater ratio of GFP-reporter mean fluorescence intensity over mCherry-reporter mean fluorescence intensity (“GFP gMFI / mCherry gMFI”) than the enhancer/core promoter constructs with a H4-specific enhancer (SEQ ID NO: 360) or the inactive enhancer (SEQ ID NO: 361). As further shown in FIG.37B, fold activation of transcription was higher when the core promoters were paired with HepG2 cell type-specific enhancers in HepG2 cells than when paired with H4 cell-type specific enhancers in HepG2 cells, suggesting that the core promoters selectively initiated transcription in the presence of liver-specific enhancers specific to the given cell type (e.g., here a liver cell-type) while exhibiting low transcriptional activation in the presence of enhancers specific for other cell types. As shown in FIG.37A, fold activation of transcription was lower with the enhancer/core promoter constructs comprising the liver-specific enhancer (SEQ ID NO: 362) when paired with a core promoter of SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, and SEQ ID NO: 107 than the expression constructs comprising a CNS-specific enhancer (H4 cell type-specific enhancer of SEQ ID NO: 360) when paired with the same core promoters in H4 cells. These observations suggest that the liver- specific enhancer (SEQ ID NO: 362) selectively enhanced transcription in liver cell types while exhibiting lower transcriptional enhancement in the presence of CNS cell types. [0521] As shown in FIG.38B, in HepG2 cells the enhancer/core promoter constructs comprising the HepG2-enhancer (SEQ ID NO: 362, “active enhancer”) when paired with a core promoter of SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 363, SEQ ID NO: 95, SEQ ID NO: 366, and SEQ ID NO: 107 all showed increased transcriptional activity of the active enhancer (the HepG2 enhancer of SEQ ID NO: 362) when paired with a core promoter over the inactive enhancer (SEQ ID NO: 361) when paired with a core promoter, indicated by a fold change over 1.0. Further in many of the constructs, the fold change was greater than 10-fold. The greatest fold change (around 15-fold) was seen in SEQ ID NO: 365 and SEQ ID NO: 107. -247- ^{Docket No. 421688-718021 (718WO1)} EXAMPLE 8 In Vivo Transcriptional Activity of CNS-Enhancer Candidates [0522] This example describes in vivo transcriptional activity of CNS-enhancer candidates. CNS-enhancer candidates of SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, and SEQ ID NO: 13 identified in EXAMPLE 4 as having high activity and specificity for neuronal cells were further assayed for activity and specificity in vivo. Each generated expression cassette, as illustrated in FIG.34, included an expression construct encoding a human progranulin protein (“hPGRN”) under control of a promoter comprising the CNS-enhancer candidate (SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, or SEQ ID NO: 13) and a minP variant core promoter of SEQ ID NO: 95 (“Enhancer + minP”), a WPRE3 regulatory element, and a polyA sequence. Control expression cassettes were also generated with either an RSV promoter (“RSV”) or a human synapsin promoter (“hSyn”) in place of the promoter comprising a CNS-enhancer candidate and the minP variant core promoter. [0523] Mice were injected via intracerebroventricular (ICV) injection with AAV9 virions containing expression cassettes with a promoter comprising a CNS-enhancer candidate (SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, or SEQ ID NO: 13) and a minP variant core promoter of SEQ ID NO: 95, or a control promoter (RSV promoter or human synapsin promoter). RNA transcription levels of human progranulin were compared between the promoters comprising the CNS-enhancer candidate (SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, or SEQ ID NO: 13) paired with a minP variant core promoter of SEQ ID NO: 95, the RSV promoter (“RSV”), and the human synapsin promoter (“hSyn”) in either brain tissue (FIG.35A) or liver tissue (FIG.35B). In FIG.35A and FIG.35B, the mRNA transcription levels were normalized to GAPDH expression. As shown in FIG.35A, CNS-enhancer candidates SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, and SEQ ID NO: 13 showed expression of progranulin in brain tissue (“hPGRN RNA expression”). As shown in FIG.35B, the CNS-enhancer candidates, SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, and SEQ ID NO: 13 showed lower progranulin expression in liver tissue than RSV. Also, shown in FIG.35B, the CNS-enhancer candidates SEQ ID NO: 14 and SEQ ID NO: 13 showed expression of progranulin in liver tissue (“hPGRN RNA expression” on y-axis), showing their expression activity in both brain and liver tissues. [0524] Human progranulin protein levels (“hPGRN protein level” on y-axis) were also compared between the promoters comprising a CNS-enhancer candidate (SEQ ID NO: 4, SEQ -248- ^{Docket No. 421688-718021 (718WO1)} ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, or SEQ ID NO: 13) paired with a minP variant core promoter of SEQ ID NO: 95, the RSV promoter (“RSV”), and the human synapsin promoter (“hSyn”) in either cerebrospinal fluid (CSF) (FIG.35C) or serum (FIG. 35D). As shown in FIG.35C, CNS-enhancer candidates SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 15, SEQ ID NO: 14, SEQ ID NO: 13, and SEQ ID NO: 4 and SEQ ID NO: 15 (“SEQ ID NOs: 4 + 15”) had increased human progranulin protein levels in cerebrospinal fluid (CSF) (“hPGRN protein level” on y-axis) compared to controls. As shown in FIG.35D, the CNS-enhancer candidates SEQ ID NO: 14 and SEQ ID NO: 13 had increased human progranulin protein levels in serum (“hPGRN protein level” on y-axis), showing their expression activity in CSF and serum. [0525] Additionally, a combined enhancer of SEQ ID NO: 244 that includes the sequences of SEQ ID NO: 4 and SEQ ID NO: 15 was also tested. An expression cassette was generated for SEQ ID NO: 244. The expression cassette, as illustrated in FIG.34, included an expression construct encoding a human progranulin protein (“hPGRN”) under control of a promoter comprising the CNS-enhancer candidate (SEQ ID NO: 244) and a minP variant core promoter of SEQ ID NO: 95 (“Enhancer + minP”), a WPRE3 regulatory element, and a polyA sequence. Control expression cassettes were also generated with either an RSV promoter or a human synapsin promoter in place of the promoter comprising a CNS-enhancer candidate and the minP variant core promoter. [0526] Mice were injected via intracerebroventricular (ICV) injection with AAV9 virions containing expression cassettes with a promoter comprising a CNS-enhancer candidate (SEQ ID NO: 244) and a minP variant core promoter of SEQ ID NO: 95, or a control promoter (RSV promoter or human synapsin promoter). RNA transcription levels of human progranulin were compared between the promoters comprising the CNS-enhancer candidate (SEQ ID NO: 244) paired with a minP variant core promoter of SEQ ID NO: 95, the RSV promoter (“RSV”), and the human synapsin promoter (“hSyn”) in either brain tissue or liver tissue. Human progranulin expression levels were also compared between the promoters comprising a CNS-enhancer candidate (SEQ ID NO: 244) paired with a minP variant core promoter of SEQ ID NO: 95, the RSV promoter (“RSV”), and the human synapsin promoter (“hSyn”) in either cerebrospinal fluid (CSF) or serum. EXAMPLE 9 Improved Payload Expression with Inclusion of a Transcriptional Pause Site [0527] This example describes the effect of a transcriptional pause site on payload expression. Expression plasmids including a normalization expression cassette encoding luciferase and a -249- ^{Docket No. 421688-718021 (718WO1)} progranulin expression cassette encoding progranulin under control of a CNS-enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a transcriptional pause site of SEQ ID NO: 311, and expression plasmids encoding a progranulin expression cassette encoding progranulin under control of a CNS-enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a transcriptional pause site of SEQ ID NO: 311 are tested. These plasmids are transfected into H4 progranulin knockout cells, and secreted progranulin protein levels are measured in the cell supernatant. Progranulin expression is higher for expression plasmids having the transcriptional pause site than for expression plasmids without the transcriptional pause site. It is expected that the transcriptional pause site increases progranulin expression by reducing transcriptional silencing due to transcriptional readthrough from the upstream promoter. [0528] This example describes the effect of a transcriptional pause site on progranulin expression. AAV containing an expression cassette including a normalization expression cassette encoding luciferase and a progranulin expression cassette encoding progranulin under control of a CNS-enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a transcriptional pause site of SEQ ID NO: 311, and expression plasmids encoding a progranulin expression cassette encoding progranulin under control of a CNS-enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a transcriptional pause site of SEQ ID NO: 311 are tested. These AAV are injected intravenously into mice and secreted progranulin protein levels are measured in the serum and CSF. Progranulin expression is higher for expression cassettes having the transcriptional pause site than for expression plasmids without the transcriptional pause site. It is expected that the transcriptional pause site increases progranulin expression by reducing transcriptional silencing in vivo. EXAMPLE 10 Improved Payload Expression with Inclusion of a Post-Transcriptional Regulatory Element [0529] This example describes the effect of a post-transcriptional regulatory element on payload expression. Expression plasmids including a normalization expression cassette encoding luciferase and a progranulin expression cassette encoding progranulin under control of a CNS- enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a post-transcriptional regulatory element of SEQ ID NO: 288, and expression plasmids encoding a progranulin expression cassette encoding progranulin under control of a CNS- enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a post-transcriptional regulatory element of SEQ ID NO: 288 are tested. These plasmids -250- ^{Docket No. 421688-718021 (718WO1)} are transfected into H4 progranulin knockout cells, and secreted progranulin protein levels are measured in the cell supernatant. Progranulin expression is higher for expression plasmids having the post-transcriptional regulatory element than for expression plasmids without the post- transcriptional regulatory element. [0530] This example describes the effect of a post-transcriptional regulatory element on progranulin expression. AAV containing an expression cassette including a normalization expression cassette encoding luciferase and a progranulin expression cassette encoding progranulin under control of a CNS-enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a post-transcriptional regulatory element of SEQ ID NO: 288, and expression plasmids encoding a progranulin expression cassette encoding progranulin under control of a CNS-enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a post-transcriptional regulatory element of SEQ ID NO: 288 are tested. These AAV are injected intravenously into mice and secreted progranulin protein levels are measured in the serum and CSF. Progranulin expression is higher for expression cassettes having the post-transcriptional regulatory element than for expression plasmids without the post-transcriptional regulatory element. EXAMPLE 11 Improved Payload Expression with Inclusion of a Polyadenylation Signal [0531] This example describes the effect of a polyadenylation signal on payload expression. Expression plasmids including a normalization expression cassette encoding luciferase and a progranulin expression cassette encoding progranulin under control of a CNS-enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a polyadenylation signal of SEQ ID NO: 299, and expression plasmids encoding a progranulin expression cassette encoding progranulin under control of a CNS-enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a polyadenylation signal of SEQ ID NO: 299 are tested. These plasmids are transfected into H4 progranulin knockout cells, and secreted progranulin protein levels are measured in the cell supernatant. Progranulin expression is higher for expression plasmids having the polyadenylation signal than for expression plasmids without the polyadenylation signal. [0532] This example describes the effect of a polyadenylation signal on progranulin expression. AAV containing an expression cassette including a normalization expression cassette encoding luciferase and a progranulin expression cassette encoding progranulin under control of a CNS- enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a polyadenylation signal of SEQ ID NO: 299, and expression plasmids encoding a -251- ^{Docket No. 421688-718021 (718WO1)} progranulin expression cassette encoding progranulin under control of a CNS-enhancer of SEQ ID NO: 3 and a minP variant core promoter of SEQ ID NO: 95, with or without a polyadenylation signal of SEQ ID NO: 299 are tested. These AAV are injected intravenously into mice and secreted progranulin protein levels are measured in the serum and CSF. Progranulin expression is higher for expression cassettes having the polyadenylation signal than for expression plasmids without the polyadenylation signal. EXAMPLE 12 In vitro and Ex Vivo Expression of Progranulin in Cultured Cells [0533] This example describes in vitro and ex vivo expression of progranulin in various cultured cell lines. Cultured cells are transfected with a progranulin expression cassette encoding human progranulin under transcriptional control of a core promoter and a CNS-enhancer (SEQ ID NO: 312). The cultured cells are H4 progranulin knockout cells, induced pluripotent stem cells (iPSCs) derived neurons of human patients having a condition associated with progranulin or a progranulin knockout line, or mouse primary neurons from wild type and progranulin knockout mice. Secreted progranulin protein levels, measured in the supernatant of the cultured cells, are evaluated. Progranulin concentrations in the cell supernatant are comparable to or greater than those produced by wild type cells expressing endogenous progranulin are targeted. [0534] Additional in vitro and ex vivo expression of progranulin in various cultured cell lines are tested. Ex vivo cultures are of primary mouse neurons (wild-type background). The in vitro cultures are of progranulin knockout human iPSC-derived neurons (wild-type GRN background engineered to knock-out both GRN copies) and a HEPG2 cell line. Secreted progranulin protein levels, measured in the supernatant of the cultured cells, are evaluated. Progranulin concentrations in the cell supernatant comparable to or greater than those produced by wild type cells expressing endogenous progranulin are targeted. EXAMPLE 13 In Vivo Expression of Progranulin in Progranulin Knockout Mice [0535] This example describes in vivo expression of human progranulin that secretes into the cerebrospinal fluid, serum, brain tissue, and liver tissue of progranulin knockout mice. Experiments were performed in about 10-month old wild type and progranulin knockout mice. PhP.eB AAVs were generated by triple transient transfection using a plasmid of SEQ ID NO: 355 (comprising human progranulin under the transcriptional control of a CNS enhancer of SEQ ID NO: 4 paired with a core promoter of SEQ ID NO: 95), SEQ ID NO: 388 (comprising human progranulin under the transcriptional control of an RSV enhancer of SEQ ID NO: 387), or a -252- ^{Docket No. 421688-718021 (718WO1)} negative control plasmid comprising an expression cassette that did not encode human progranulin. SEQ ID NO: 355 comprises SEQ ID NO: 312. [0536] AAVs produced using each of the above described plasmids (e.g., SEQ ID NO: 355, SEQ ID NO: 388, and a negative control plasmid) were administered to progranulin knockout mice via tail vein injection, and progranulin protein levels were measured in cerebrospinal fluid (CSF), serum, brain tissue, and liver tissue. [0537] Forty progranulin knockout mice (20 male and 20 female) and 20 wildtype C57BL/6 mice (10 male and 10 female) were used for the study. Progranulin levels in cerebrospinal fluid (CSF) of 10-30 ng/mL were targeted. AAV dosing was adjusted to achieve target progranulin expression levels in CSF. AAVs produced using the plasmid of SEQ ID NO: 388, the plasmid encoding progranulin (GRN) under control of an RSV promoter (SEQ ID NO: 387), were administered to progranulin knockout mice at a dosage of 7.5E10 (vg). AAVs produced using the plasmid of SEQ ID NO: 355, the plasmid encoding progranulin (GRN) under control of a promoter comprising a CNS-enhancer of SEQ ID NO: 4 and a core promoter of SEQ ID NO: 95, were administered to progranulin knockout mice at a dosage of 1E11 (vg). AAVs produced using the negative control plasmid (did not encode for progranulin) were administered to progranulin knockout mice at a dosage of 7.5E10 (vg) and also were administered to wildtype c57 mice. Untreated progranulin knockout mice and wildtype C57BL/6 mice were also included in the study for an untreated control. Two months post-AAV injection, the tissue and fluids were collected from the mice. [0538] For serum collection, mice were anesthetized using 2-3% isoflurane in air with O2 supplement. The whole blood was collected by retro-orbital bleed using capillary tubes. Up to 200 uL of blood was collected and placed in a serum separator tube. After collection, serum tubes were centrifuged for 10 minutes at 10,000xG and serum samples were stored at -80°C. For CSF collection, mice were euthanized with CO2 or isoflurane immediately before CSF extraction. CSF samples were collected from the cisterna magna of euthanized mice using a 30G needle. Up to 10 ul of CSF was collected in a 1.5 ml eppendorf tube and stored at –80C. [0539] For brain tissue collection, both hemispheres (brain weight approximately 400 mg) were collected from each animal. Left and right hemispheres were separated and collected into cryovials, left hemisphere was snap frozen in liquid nitrogen and stored at -80°C, while the right hemisphere was collected in 4% paraformaldehyde (PFA) for histology processing. Brains were then processed for DNA and RNA extraction for ddPCR analysis, and for protein to measure human progranulin levels in tissue. -253- ^{Docket No. 421688-718021 (718WO1)} [0540] For liver tissue collection, two small pieces of the right lobe of the liver (approximately 100 mg) were collected. Both samples were placed into cryovials and snap-frozen in liquid nitrogen for DNA and RNA extraction and ddPCR analysis, and for protein to measure human progranulin levels in tissue. [0541] Human progranulin RNA expression in brain tissue and liver tissue were quantified by ddPCR. Human progranulin protein expression in serum and cerebrospinal fluid (CSF) were quantified by enzyme-linked immunosorbent assay (ELISA) measuring hGRN. The ELISA method used does not detect mouse PGRN and would only detect human PGRN (hGRN) expressed from the payload. [0542] As shown in FIG.39A and FIG.40A, in serum, the injections of AAV produced using a plasmid of SEQ ID NO: 388 or SEQ ID NO: 355 showed human progranulin (“PGRN”) expression 8 weeks post-injection of progranulin knockout mice (“PGRN KO”). Also shown in FIG.39A and FIG.40A, the negative control vector and the untreated control did not show any progranulin expression in the serum of progranulin knockout mice (“PGRN KO”) or the wildtype mice (“WT). [0543] As shown in FIG.39B and FIG.40B, in cerebrospinal fluid (CSF) the injections of AAV produced using a plasmid of SEQ ID NO: 388 showed human progranulin (“PGRN”) expression in cerebrospinal fluid (CSF) 8 weeks post-injection of progranulin knockout mice (“PGRN KO”). Also shown in FIG.39B and FIG.40B, the negative control vector (“negative control”) and the untreated control (“untreated control”) did not show any progranulin expression in cerebrospinal fluid (CSF) of the progranulin knockout mice (“PGRN KO”) or the wildtype mice (“WT). Though the injections of AAV produced using a plasmid of SEQ ID NO: 355 did not show human progranulin (“PGRN”) expression in cerebrospinal fluid (CSF) 8 weeks post- injection of progranulin knockout mice (“PGRN KO”), as shown in FIG.39B and FIG.40B (which was likely due to a titering issue of the AAV produced using a plasmid of SEQ ID NO: 355), other data discussed below (e.g., the data shown in FIG.41B, FIG.42B, FIG.43B, and FIG.45) does show human progranulin (“PGRN”) expression in brain tissue from the injections of AAV produced using a plasmid of SEQ ID NO: 355. [0544] As shown in FIG.41A and FIG.42A, in liver tissue, the injections of AAV produced using a plasmid of SEQ ID NO: 388 showed human progranulin (“PGRN”) expression 8 weeks post-injection of progranulin knockout mice (“PGRN KO”) while the injections of AAV produced using a plasmid of SEQ ID NO: 355 did not show progranulin expression in liver tissue. These data demonstrate that the CNS-enhancer of SEQ ID NO: 4 paired with the core promoter of SEQ ID NO: 95 had minimal, if any, off-target progranulin expression in the liver. -254- ^{Docket No. 421688-718021 (718WO1)} Also shown in FIG.41A and FIG.42A, the negative control vector and the untreated control did not show any progranulin expression in the liver tissue of progranulin knockout mice (“PGRN KO”) or the wildtype mice (“WT). FIG.42A also shows that the progranulin protein measured in the liver of the mice injected with AAV produced using a plasmid of SEQ ID NO: 388 differed between the male and female mice, which is consistent with previous reports by others that AAV transduction in the liver is influenced by androgen production, and therefore, there is a difference between male and female AAV transduction in the liver (higher testosterone in male mice likely causes higher transduction in liver compared to female mice). This sex difference is also thought to extend to peripheral tissues, such as serum, which is consistent with the sex differences seen in FIG.39A and FIG.40A. [0545] As shown in FIG.41B and FIG.42B, in brain tissue, the injections of AAV produced using a plasmid of SEQ ID NO: 388 or SEQ ID NO: 355 showed human progranulin (“PGRN”) expression 8 weeks post-injection of progranulin knockout mice (“PGRN KO”). These data demonstrate that the CNS-enhancer of SEQ ID NO: 4 paired with the core promoter of SEQ ID NO: 95, showed CNS-specific expression of the progranulin payload. Also shown in FIG.41B and FIG.42B, the negative control vector and the untreated control did not show any progranulin expression in the brain tissue of progranulin knockout mice (“PGRN KO”) or the wildtype mice (“WT). [0546] The progranulin expression in brain and liver tissues was also evaluated for transduction efficiency. The transduction efficiency was measured by the quantification of the vector genome per diploid genome (vg/dg), in which the viral genomes were normalized against mouse transferrin receptor (mTFRC) for the calculating the vg/dg values. As shown in FIG.43A, in liver-tissue, the AAV transduction for AAV produced using a plasmid of SEQ ID NO: 388 or SEQ ID NO: 355 were similar and there were higher levels of transduction in male progranulin knockout mice (“GRN KO”) than female progranulin knockout mice (“GRN KO”). As shown in FIG.43B, in brain tissue, the AAV transduction for AAV produced using a plasmid of SEQ ID NO: 388 or SEQ ID NO: 355 were similar, and no sex differences in the levels of transduction was seen. Notably, the sex differences seen in FIG.43A for the liver were not seen in FIG.43B for the brain, indicating that the sex differences in progranulin expression in FIG.43A is due to differences in androgen production/AAV transduction and not related to promoters, which also extends to the sex differences seen in FIG.40A and FIG.42B. [0547] The transduction efficiencies were then correlated with the progranulin protein expressed for the AAV injections in the liver (FIG.44) and the brain (FIG.45). As shown in FIG.44 and FIG.45, the AAV transduction for AAV produced using a plasmid of SEQ ID NO: 388 -255- ^{Docket No. 421688-718021 (718WO1)} correlated with the progranulin protein expression in both the brain and liver tissues of progranulin knockout mice (“GRN KO”). Also shown in FIG.44 and FIG.45, the AAV transduction for AAV produced using a plasmid of SEQ ID NO: 355 correlated with the progranulin protein expression in the brain tissue but did not correlate to progranulin expression in the liver tissue, demonstrating the CNS-specificity of the CNS-enhancer (SEQ ID NO: 4) paired with the core promoter (SEQ ID NO: 95). EXAMPLE 14 Expression of Progranulin in Cerebrospinal Fluid of Non-Human Primates [0548] This example describes expression of progranulin in cerebrospinal fluid and serum of non-human primates (NHPs). AAV comprising SEQ ID NO: 312 are intravenously administered to a non-human primate at a dosage of 8.7E12 vg/kg, and progranulin protein levels are measured in cerebrospinal fluid (CSF) and serum extracted from the non-human primate weekly for eight weeks following AAV administration. Human progranulin is detected in CSF and serum. The biodistribution and expression is also evaluated using ddPCR and in situ hybridization. The immunogenicity of the expressed human progranulin is also evaluated. EXAMPLE 15 Liver-Specific Expression in Non-Human Primates [0549] This example describes the liver-specific expression of a payload in non-human primates (NHPs) in AAV-delivered payloads under the transcriptional control of a liver-enhancer paired with a core promoter. AAV vectors were designed with an expression cassette comprising a payload under the transcriptional control of either a control promoter, comprising a sequence of SEQ ID NO: 389, or a liver-specific promoter comprising the liver-enhancer of SEQ ID NO: 362 paired with the core promoter of SEQ ID NO: 95. The AAV vectors further comprised two barcode sequences for analysis: one barcode was to measure the capsid sequence and the other barcode was to measure the promoter. Two non-human primates were injected with about ~10,000 capsid variants and 5 wildtype serotypes. Each of the wildtype serotypes were dosed in 3 dose levels (each 1x, 10, 100x with respect to the variants tested). The non-human primates were injected IV and their tissues were collected at day 29. [0550] FIG.46 shows the abundance of the control promoter (“Control”; SEQ ID NO: 389) compared to the abundance of the liver-specific promoter (“Liver-Specific”; comprising the liver-enhancer of SEQ ID NO: 362 paired with the core promoter of SEQ ID NO: 95) in wildtype (WT) serotypes dosed at 100x. The abundance of the promoters was measured by the ratio of Control/Liver-Specific abundance as a log2(ratio) after normalizing RNA by -256- ^{Docket No. 421688-718021 (718WO1)} corresponding DNA abundances in either heart tissue or liver tissue. As seen in FIG.46, there was higher expression seen by the liver-specific promoter (“Liver-Specific”; comprising the liver-enhancer of SEQ ID NO: 362 paired with the core promoter of SEQ ID NO: 95) compared to the expression by the control promoter (SEQ ID NO: 389) in non-human primate liver than in non-human primate heart for 4 of the 5 tested wildtype serotypes. It was suspected that the 1 serotype (AAV1) with the opposite trend may be due to noise in the dataset stemming from variability in readouts from the primary tissue in a small number of animals. Therefore, this data indicates that the liver-specific promoter (comprising the liver-enhancer of SEQ ID NO: 362 paired with the core promoter of SEQ ID NO: 95) has greater liver specific expression than the control promoter (SEQ ID NO: 389). EXAMPLE 16 Expression of Progranulin in Cerebrospinal Fluid of Non-Human Primates [0551] This example describes expression of progranulin in cerebrospinal fluid of non-human primates. Engineered AAV5 virions assembled from VP capsid polypeptides comprising a 581- 589 region sequence of SEQ ID NO: 321 and encapsidating an expression cassette encoding human progranulin under transcriptional control of a core promoter and a CNS-enhancer (SEQ ID NO: 312) are generated. The expression cassette encodes human progranulin under transcriptional control of core promoter of SEQ ID NO: 95 and a CNS-enhancer of SEQ ID NO: 4. The engineered AAV5 virions are intravenously administered to a non-human primate, and progranulin protein levels are measured in cerebrospinal fluid (CSF) and serum extracted from the non-human primate weekly for eight weeks following AAV administration. Human progranulin is detected in CSF and serum. AAV dosing is adjusted to achieve a target progranulin expression level in CSF and a target progranulin expression level in serum. Tissue distribution is also assessed. EXAMPLE 17 Expression of Progranulin in Cerebrospinal Fluid of Non-Human Primates [0552] This example describes expression of progranulin in cerebrospinal fluid of non-human primates. Engineered AAV5 virions assembled from VP capsid polypeptides comprising a 581- 589 region sequence of SEQ ID NO: 322 and encapsidating an expression cassette encoding human progranulin under transcriptional control of a core promoter and a CNS-enhancer (SEQ ID NO: 312) are generated. The expression cassette encodes human progranulin under transcriptional control of core promoter of SEQ ID NO: 95 and a CNS-enhancer of SEQ ID NO: 4. The engineered AAV5 virions are intravenously administered to a non-human primate, and progranulin protein levels are measured in cerebrospinal fluid (CSF) and serum extracted from -257- ^{Docket No. 421688-718021 (718WO1)} the non-human primate weekly for eight weeks following AAV administration. Human progranulin is detected in CSF and serum. AAV dosing is adjusted to achieve a target progranulin expression level in CSF and a target progranulin expression level in serum. Tissue distribution is also assessed. EXAMPLE 18 Expression of Progranulin in Cerebrospinal Fluid of Non-Human Primates [0553] This example describes expression of progranulin in cerebrospinal fluid of non-human primates. Engineered AAV5 virions assembled from VP capsid polypeptides comprising a 581- 589 region sequence of any one of SEQ ID NO: 320 or SEQ ID NO: 323 – SEQ ID NO: 349 and encapsidating an expression cassette encoding human progranulin under transcriptional control of a core promoter and a CNS-enhancer (SEQ ID NO: 312) are generated. The expression cassette encodes human progranulin under transcriptional control of core promoter of SEQ ID NO: 95 and a CNS-enhancer of SEQ ID NO: 4. The engineered AAV5 virions are intravenously administered to a non-human primate, and progranulin protein levels are measured in cerebrospinal fluid (CSF) and serum extracted from the non-human primate weekly for eight weeks following AAV administration. Progranulin levels in CSF of at least 3 ng/mL are targeted. Human progranulin is detected in CSF and serum. AAV dosing is adjusted to achieve a target progranulin expression level in CSF and a target progranulin expression level in serum. Tissue distribution is also assessed. EXAMPLE 19 Excitatory Neuron-Specific Transcription of Exogenous Progranulin in the Central Nervous System [0554] This example describes transcription of an CNS-specific exogenous progranulin in the central nervous system (CNS). A CNS-specific progranulin DNA construct containing a progranulin coding sequence, a CNS-specific enhancer of any one of SEQ ID NO: 1 – SEQ ID NO: 20, and a core promoter is constructed. The CNS-specific enhancer is selected from SEQ ID NO: 1 – SEQ ID NO: 20 or SEQ ID NO: 41 – SEQ ID NO: 60. The progranulin construct is encapsidated in an adeno-associated virus and delivered to cells of a subject. Optionally, the progranulin construct is integrated into a recombinant polynucleotide cassette comprising one or more of a 5’UTR effector region, 3’UTR effector region, codon optimized progranulin sequence, or introns (natural and/or synthetic) for modulating translation of the RNA coding for progranulin before being encapsidated for AAV delivery. Optionally, the polynucleotide cassette comprises a sequence of SEQ ID NO: 312. The exogenous progranulin encoded by the progranulin construct is transcribed at higher levels in excitatory neurons than in other non- -258- ^{Docket No. 421688-718021 (718WO1)} neuronal cell types or non-CNS tissue, including hepatocytes or liver tissue. CNS-specific transcription of the progranulin transgene results in CNS-specific expression of the exogenous progranulin. [0555] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. -259- ^{Docket No. 421688-718021 (718WO1)}

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter.

2. The recombinant polynucleotide of claim 1, wherein the enhancer comprises a sequence having at least 90% sequence identity to SEQ ID NO: 4, or a reverse complement thereof.

3. The recombinant polynucleotide of claim 1, wherein the enhancer comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof.

4. A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof; and a core promoter.

5. The recombinant polynucleotide of claim 4, wherein the enhancer comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof.

6. The recombinant polynucleotide of claim 4, wherein the enhancer comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof.

7. The recombinant polynucleotide of any one of claims 1-6, further comprising a payload, wherein: the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein. -260- ^{Docket No. 421688-718021 (718WO1)}

8. The recombinant polynucleotide of claim 7, wherein the promoter enhances the transcription of the payload in a target tissue.

9. The recombinant polynucleotide of claim 8, wherein the target tissue is a central nervous system tissue.

10. The recombinant polynucleotide of claim 9, wherein the transcription is enhanced in the central nervous system tissue as compared to a kidney tissue.

11. The recombinant polynucleotide of claim 9 or claim 10, wherein the transcription is enhanced in the central nervous system tissue as compared to a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.

12. The recombinant polynucleotide of any one of claims 1-11, further comprising a post- transcriptional regulatory element.

13. The recombinant polynucleotide of any one of claims 1-12, further comprising a polyadenylation signal.

14. The recombinant polynucleotide of any one of claims 1-13, further comprising a transcriptional pause site.

15. A recombinant polynucleotide comprising: a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof, and a core promoter capable of binding to a polymerase; a coding sequence operably linked to the promoter; a post-transcriptional regulatory element; a polyadenylation signal; and a transcriptional pause site.

16. The recombinant polynucleotide of claim 15, wherein the enhancer comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 4, or a reverse complement thereof.

17. The recombinant polynucleotide of claim 15, wherein the enhancer comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 4, or a reverse complement thereof. -261- ^{Docket No. 421688-718021 (718WO1)}

18. The recombinant polynucleotide of any one of claims 7-17, wherein the coding sequence encodes a progranulin.

19. The recombinant polynucleotide of any one of claims 1-18, wherein the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof.

20. The recombinant polynucleotide of any one of claims 1-19, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366.

21. The recombinant polynucleotide of any one of claims 1-20, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95.

22. The recombinant polynucleotide of any one of claims 1-21, wherein the core promoter is a sequence of SEQ ID NO: 95.

23. The recombinant polynucleotide of any one of claims 12-22, wherein the post- transcriptional regulatory element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 287 or SEQ ID NO: 288.

24. The recombinant polynucleotide of any one of claims 12-23, wherein the post- transcriptional regulatory element comprises a sequence of SEQ ID NO: 288.

25. The recombinant polynucleotide of any one of claims 12-24, wherein the post- transcriptional regulatory element is downstream of the coding sequence.

26. The recombinant polynucleotide of any one of claims 13-25, wherein the polyadenylation signal comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 297 – SEQ ID NO: 306.

27. The recombinant polynucleotide of any one of claims 13-26, wherein the polyadenylation signal comprises a sequence of SEQ ID NO: 299. -262- ^{Docket No. 421688-718021 (718WO1)}

28. The recombinant polynucleotide of any one of claims 13-27, wherein the polyadenylation signal is downstream of the coding sequence.

29. The recombinant polynucleotide of any one of claims 14-28, wherein the transcriptional pause site comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 311.

30. The recombinant polynucleotide of any one of claims 14-29, wherein the transcriptional pause site comprises a sequence of SEQ ID NO: 311.

31. The recombinant polynucleotide of any one of claims 14-30, wherein the transcriptional pause site is downstream of the coding sequence.

32. The recombinant polynucleotide of any one of claims 14-31, wherein the transcriptional pause site is downstream of the polyadenylation signal.

33. The recombinant polynucleotide of any one of claims 14-32, wherein the coding sequence is downstream of the promoter, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post- transcriptional regulatory element, and the transcriptional pause site is downstream of the post- transcriptional regulatory element.

34. The recombinant polynucleotide of any one of claims 14-33, wherein the coding sequence is downstream of the promoter, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post- transcriptional regulatory element, and the transcriptional pause site is downstream of the polyadenylation signal.

35. The recombinant polynucleotide of any one of claims 1-34, further comprising a neuron- restrictive silencer element.

36. The recombinant polynucleotide of claim 35, wherein the neuron-restrictive silencer element comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289 – SEQ ID NO: 296.

37. The recombinant polynucleotide of any one of claims 1-36, further comprising a CCCTC-binding factor sequence. -263- ^{Docket No. 421688-718021 (718WO1)}

38. The recombinant polynucleotide of claim 37, wherein the CCCTC-binding factor sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO: 293, or SEQ ID NO: 295.

39. The recombinant polynucleotide of any one of claims 1-38, further comprising a stuffer sequence.

40. The recombinant polynucleotide of claim 39, wherein the stuffer sequence comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 309.

41. The recombinant polynucleotide of claim 39 or claim 40, wherein the stuffer sequence comprises a sequence of SEQ ID NO: 309.

42. The recombinant polynucleotide of any one of claims 39-41, wherein the stuffer sequence is upstream of the coding sequence.

43. The recombinant polynucleotide of any one of claims 39-42, wherein the stuffer sequence is upstream of the promoter.

44. The recombinant polynucleotide of any one of claims 39-43, wherein the stuffer sequence is upstream of the promoter, the coding sequence is downstream of the promoter, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post-transcriptional regulatory element, and the transcriptional pause site is downstream of the polyadenylation signal.

45. The recombinant polynucleotide of any one of claims 1-44, further comprising a 5’ untranslated region.

46. The recombinant polynucleotide of claim 45, wherein the 5’ untranslated region comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 310, SEQ ID NO: 353, or SEQ ID NO: 354.

47. The recombinant polynucleotide of claim 45, wherein the 5’ untranslated region comprises a sequence of SEQ ID NO: 310.

48. The recombinant polynucleotide of claim 45, wherein the 5’ untranslated region comprises a sequence of SEQ ID NO: 353. -264- ^{Docket No. 421688-718021 (718WO1)}

49. The recombinant polynucleotide of any one of claims 45-48, wherein the 5’ untranslated region is upstream of the coding sequence.

50. The recombinant polynucleotide of any one of claims 45-49, wherein the 5’ untranslated region is downstream of the promoter.

51. The recombinant polynucleotide of any one of claims 45-50, wherein the stuffer sequence is upstream of the promoter, the 5’ untranslated region is downstream of the promoter, the coding sequence is downstream of the 5’ untranslated region, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post-transcriptional regulatory element, and the transcriptional pause site is downstream of the polyadenylation signal.

52. The recombinant polynucleotide of any one of claims 1-51, further comprising a 5’ inverted terminal repeat upstream of the promoter.

53. The recombinant polynucleotide of claim 52, wherein the 5’ inverted terminal repeat is upstream of the stuffer sequence.

54. The recombinant polynucleotide of claim 52 or claim 53, wherein the 5’ inverted terminal repeat is an AAV55’ inverted terminal repeat, an AAV15’ inverted terminal repeat, an AAV2 5’ inverted terminal repeat, an AAV95’ inverted terminal repeat, or a PhP.eB 5’ inverted terminal repeat.

55. The recombinant polynucleotide of any one of claims 52-54, wherein the 5’ inverted terminal repeat is an AAV 5’ inverted terminal repeat.

56. The recombinant polynucleotide of claim 55, wherein the AAV 5’ inverted terminal repeat is a single stranded AAV 5’ inverted terminal repeat.

57. The recombinant polynucleotide of any one of claims 52-56, wherein the 5’ inverted terminal repeat is an AAV25’ inverted terminal repeat.

58. The recombinant polynucleotide of claim 57, wherein the AAV25’ inverted terminal repeat is a single stranded AAV25’ inverted terminal repeat.

59. The recombinant polynucleotide of any one of claims 52-58, wherein the 5’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 307. -265- ^{Docket No. 421688-718021 (718WO1)}

60. The recombinant polynucleotide of any one of claims 52-59, wherein the 5’ inverted terminal repeat comprises a sequence of SEQ ID NO: 307.

61. The recombinant polynucleotide of any one of claims 14-60, further comprising a 3’ inverted terminal repeat downstream of the transcriptional pause site.

62. The recombinant polynucleotide of claim 61, wherein the 3’ inverted terminal repeat is an AAV 3’ inverted terminal repeat.

63. The recombinant polynucleotide of claim 62, wherein the AAV 3’ inverted terminal repeat is a single stranded AAV 3’ inverted terminal repeat.

64. The recombinant polynucleotide of any one of claims 61-63, wherein the 3’ inverted terminal repeat is an AAV53’ inverted terminal repeat, an AAV13’ inverted terminal repeat, an AAV2 3’ inverted terminal repeat, an AAV93’ inverted terminal repeat, or a PhP.eB 3’ inverted terminal repeat.

65. The recombinant polynucleotide of any one of claims 61-64, wherein the 3’ inverted terminal repeat is an AAV23’ inverted terminal repeat.

66. The recombinant polynucleotide of claim 65, wherein the AAV23’ inverted terminal repeat is a single stranded AAV23’ inverted terminal repeat.

67. The recombinant polynucleotide of any one of claims 61-66, wherein the 3’ inverted terminal repeat comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 308.

68. The recombinant polynucleotide of any one of claims 61-67, wherein the 3’ inverted terminal repeat comprises a sequence of SEQ ID NO: 308.

69. The recombinant polynucleotide of any one of claims 61-68, wherein the 5’ inverted terminal repeat is upstream of the stuffer sequence, the stuffer sequence is upstream of the promoter, the 5’ untranslated region is downstream of the promoter, the coding sequence is downstream of the 5’ untranslated region, the post-transcriptional regulatory element is downstream of the coding sequence, the polyadenylation signal is downstream of the post- transcriptional regulatory element, the transcriptional pause site is downstream of the polyadenylation signal, and the 3’ inverted terminal repeat downstream of the transcriptional pause site. -266- ^{Docket No. 421688-718021 (718WO1)}

70. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4 and (ii) SEQ ID NO 95.

71. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; and (iii) SEQ ID NO: 350.

72. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; and (iv) SEQ ID NO: 288.

73. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; and (iv) SEQ ID NO: 299.

74. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; (iv) SEQ ID NO: 288; and (v) SEQ ID NO: 299.

75. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; and (iv) SEQ ID NO: 311.

76. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 350; (iv) SEQ ID NO: 288; (v) SEQ ID NO: 299; and (vi) SEQ ID NO: 311.

77. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; (iii) SEQ ID NO: 353; (iv) SEQ ID NO: 350; (v) SEQ ID NO: 288; (vi) SEQ ID NO: 299; and (vii) SEQ ID NO: 311.

78. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 4; (ii) SEQ ID NO 95; and (iii) SEQ ID NO: 353.

79. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; and (v) SEQ ID NO: 350. -267- ^{Docket No. 421688-718021 (718WO1)}

80. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; and (vii) SEQ ID NO: 299.

81. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; and (vi) SEQ ID NO: 311.

82. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 309; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; (vii) SEQ ID NO: 299; and (viii) SEQ ID NO: 311.

83. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 309; (iii) SEQ ID NO: 4; (iv) SEQ ID NO 95; (v) SEQ ID NO: 353; (vi) SEQ ID NO: 350; (vii) SEQ ID NO: 288; (viii) SEQ ID NO: 299; (ix) SEQ ID NO: 311; and (x) SEQ ID NO: 308.

84. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; and (iii) SEQ ID NO: 308.

85. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; and (iv) SEQ ID NO: 308.

86. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 350; and (v) SEQ ID NO: 308.

87. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; and (vi) SEQ ID NO: 308.

88. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID -268- ^{Docket No. 421688-718021 (718WO1)} NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; (vii) SEQ ID NO: 299; and (viii) SEQ ID NO: 308.

89. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 311; and (vii) SEQ ID NO: 308.

90. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 4; (iii) SEQ ID NO 95; (iv) SEQ ID NO: 353; (v) SEQ ID NO: 350; (vi) SEQ ID NO: 288; (vii) SEQ ID NO: 299; (viii) SEQ ID NO: 311; and (ix) SEQ ID NO: 308.

91. The recombinant polynucleotide of any one of claims 1-69, wherein the recombinant polynucleotide, from 5’ to 3’, comprises: (i) SEQ ID NO: 307; (ii) SEQ ID NO: 309; (iii) SEQ ID NO: 4; (iv) SEQ ID NO 95; (v) SEQ ID NO: 353; (vi) SEQ ID NO: 350; (vii) SEQ ID NO: 288; (viii) SEQ ID NO: 299; (ix) SEQ ID NO: 311; and (x) SEQ ID NO: 308.

92. The recombinant polynucleotide of any one of claims 1-91, wherein the recombinant polynucleotide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 312.

93. The recombinant polynucleotide of any one of claims 1-91, wherein the recombinant polynucleotide comprises a sequence having at least 80% sequence identity to SEQ ID NO: 312.

94. The recombinant polynucleotide of any one of claims 1-91, wherein the recombinant polynucleotide comprises a sequence having at least 90% sequence identity to SEQ ID NO: 312.

95. The recombinant polynucleotide of any one of claims 1-91, wherein the recombinant polynucleotide comprises a sequence of SEQ ID NO: 312.

96. The recombinant polynucleotide of any one of claims 1-91, wherein the recombinant polynucleotide is SEQ ID NO: 312.

97. The recombinant polynucleotide of any one of claims 7-96, wherein the payload encodes a protein; optionally, wherein the protein is a therapeutic protein.

98. The recombinant polynucleotide of claim 97, wherein the protein is a neuronal protein or an antibody; optionally, wherein the antibody is a therapeutic antibody. -269- ^{Docket No. 421688-718021 (718WO1)}

99. The recombinant polynucleotide of claim 97 or claim 98, wherein the protein is associated with a central nervous system disorder.

100. The recombinant polynucleotide of claim 99, wherein the central nervous system disorder is a neuronal disorder.

101. The recombinant polynucleotide of claim 99 or claim 100, wherein the central nervous system disorder is a genetic disorder.

102. The recombinant polynucleotide of any one of claims 97-101, wherein the protein is progranulin or MeCP2.

103. The recombinant polynucleotide of claim 102, wherein the progranulin is human progranulin.

104. The recombinant polynucleotide of claim 102 or claim 103, wherein the progranulin encoded by the payload comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 352.

105. The recombinant polynucleotide of claim 97, wherein the payload comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 350.

106. The recombinant polynucleotide of claim 97, wherein the payload comprises a sequence of SEQ ID NO: 350.

107. The recombinant polynucleotide of any one of claims 1-106, wherein the payload encodes a therapeutic polynucleotide.

108. The recombinant polynucleotide of claim 107, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.

109. The recombinant polynucleotide of claim 107 or claim 108, wherein the therapeutic polynucleotide targets a gene.

110. The recombinant polynucleotide of claim 109, wherein the gene is associated with a central nervous system disorder.

111. The recombinant polynucleotide of claim 110, wherein the central nervous system disorder is a neuronal disorder. -270- ^{Docket No. 421688-718021 (718WO1)}

112. The recombinant polynucleotide of claim 109 or claim 110, wherein the central nervous system disorder is a genetic disorder.

113. The recombinant polynucleotide of any one of claims 109-112, wherein the gene is GRN or MECP2.

114. A plasmid comprising the recombinant polynucleotide of any one of claims 1-113.

115. The plasmid of claim 114, comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 355.

116. An engineered viral vector comprising the recombinant polynucleotide of any one of claims 1-113.

117. The engineered viral vector of claim 116, wherein the viral vector is an adenoviral vector, an adeno-associated viral vector, or a lentivector.

118. The engineered viral vector of claim 117, wherein the adeno-associated viral vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV-DJ, AAV-DJ/8, AAV-DJ/9, AAV1/2, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh43, AAV.Rh74, AAV.v66, AAV.Oligo001, AAV.SCH9, AAV.r3.45, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PhP.eB, AAV.PhP.V1, AAV.PHP.B, AAV.PhB.C1, AAV.PhB.C2, AAV.PhB.C3, AAV.PhB.C6, AAV.cy5, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAV.HSC17, AAVhu68, and combinations thereof.

119. The engineered viral vector of claim 116 or claim 117, wherein the adeno-associated viral vector is an AAV5 vector.

120. The engineered viral vector of any one of claims 116-119, wherein the adeno-associated viral vector comprises an engineered viral protein (VP) capsid polypeptide.

121. The engineered viral vector of claim 120, wherein the engineered VP capsid polypeptide comprises at least one substitution in a VR VIII loop of an AAV. -271- ^{Docket No. 421688-718021 (718WO1)}

122. The engineered viral vector of claim 120 or claim 121, wherein the engineered VP capsid polypeptide comprises at least one substitution in a region of the engineered VP capsid polypeptide corresponding to a 581-589 region of a wild type VP capsid polypeptide of SEQ ID NO: 313.

123. The engineered viral vector of any one of claims 116-122, wherein the engineered VP capsid polypeptide comprises a formula of (A)-(X)-(B), wherein (A) is a first polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 318, (X) is the 581-589 region, and (B) is a second polypeptide having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 319.

124. A pharmaceutical composition comprising the recombinant polynucleotide of any one of claims 1-113, the plasmid of claim 114 or claim 115, or the engineered viral vector of any one of claims 116-123 and a pharmaceutically acceptable carrier.

125. A method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide to the target cell or the target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof, and a payload operably linked to the enhancer; and transcribing the payload in the target cell or the target tissue.

126. A method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide comprising a promoter to the target cell or the target tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter; and transcribing the payload in the target cell or the target tissue.

127. A method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: -272- ^{Docket No. 421688-718021 (718WO1)} delivering a recombinant polynucleotide to the target cell or the target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, and a payload operably linked to the enhancer; and transcribing the payload in the target cell or the target tissue.

128. A method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide comprising a promoter to the target cell or the target tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof; and a core promoter; and transcribing the payload in the target cell or the target tissue.

129. The method of claims 126 or 128, wherein the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof.

130. The method of any one of claims 126, 128, or 129, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366.

131. The method of any one of claims 126 or 128-130, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95.

132. The method of any one of claims 126 or 128-131, wherein the core promoter is a sequence of SEQ ID NO: 95.

133. The method of any one of claims 125-132, wherein the recombinant polynucleotide is the recombinant polynucleotide of any one of claims 1-113, or the recombinant polynucleotide -273- ^{Docket No. 421688-718021 (718WO1)} is in the plasmid of claim 114 or claim 115 or in the engineered viral vector of any one of claims 116-123.

134. The method of any one of claims 125-133, further comprising delivering the recombinant polynucleotide by administering the pharmaceutical composition of claim 124 to the subject.

135. The method of any one of claims 125-134, wherein the target tissue is a central nervous system tissue.

136. The method of any one of claims 125-135, comprising expressing the payload at a higher level in the target tissue than in a non-target tissue.

137. The method of claim 136, wherein the non-target tissue is a kidney tissue, a liver tissue, a heart tissue, a lung tissue, or a muscle tissue.

138. The method of any one of claim 136 or claim 137, wherein the target tissue comprises a target cell type, and wherein the non-target tissue comprises a non-target cell type.

139. The method of any one of claims 125-138, wherein the target cell type is a neuron or a glial cell.

140. The method of any one of claims 136-139, wherein the non-target cell type is a renal cell, a retinal cell, a hepatocyte, an epithelial cell, a muscle cell, an erythrocyte, a platelet, a bone marrow cell, an endothelial cell, an epidermal cell, a lymphocyte, an interstitial cell, an adipocyte, a fibroblast, or combinations thereof.

141. The method of any one of claims 125-140, wherein the payload encodes for progranulin.

142. The method of claim 141, wherein the progranulin is human progranulin.

143. The method of claim 141 or claim 142, comprising expressing the progranulin in a fluid secreted by the cell, tissue, or subject.

144. The method of claim 143, wherein the progranulin is expressed in the fluid at a level of not less than 1 ng/mL and not more than 100 ng/mL.

145. The method of claim 143, wherein the progranulin is expressed in the fluid at a level of not less than 10 ng/mL and not more than 100 ng/mL. -274- ^{Docket No. 421688-718021 (718WO1)}

146. The method of claim 143, wherein the progranulin is expressed in the fluid at a level of not less than 1 ng/mL and not more than 30 ng/mL.

147. The method of claim 143, wherein the progranulin is expressed in the fluid at a level of not less than 10 ng/mL and not more than 50 ng/mL.

148. The method of claim 143, wherein the progranulin is expressed in the fluid at a level of not less than 10 ng/mL and not more than 30 ng/mL.

149. The method of claim 143, wherein the progranulin is expressed in the fluid at a level of not less than 70 ng/mL and not more than 180 ng/mL.

150. The method of claim 143, wherein the progranulin is expressed in the fluid at a level of not less than 70 ng/mL and not more than 300 ng/mL.

151. The method of any one of claims 143-150, wherein the fluid comprises a cerebrospinal fluid.

152. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide to a target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof, and a payload operably linked to the enhancer; and expressing a therapeutic sequence encoded by the payload in a target tissue of the subject, thereby treating the disorder.

153. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide comprising a promoter to the target cell or the target tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof; and a core promoter; and expressing a therapeutic sequence encoded by the payload in a target tissue of the subject, thereby treating the disorder.

154. A method of treating a disorder in a subject in need thereof, the method comprising: -275- ^{Docket No. 421688-718021 (718WO1)} administering to the subject a composition comprising a recombinant polynucleotide to a target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof, and a payload operably linked to the enhancer; and expressing a therapeutic sequence encoded by the payload in a target tissue of the subject, thereby treating the disorder.

155. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide comprising a promoter to the target cell or the target tissue in a subject, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to any one of SEQ ID NO: 1 – SEQ ID NO: 80, SEQ ID NO: 237 – SEQ ID NO: 286, SEQ ID NO: 360, or SEQ ID NO: 385, or a reverse complement thereof; and a core promoter; and expressing a therapeutic sequence encoded by the payload in a target tissue of the subject, thereby treating the disorder.

156. The method of claims 153 or 155, wherein the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof.

157. The method of claims 153 or 155, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366.

158. The method of claims 153 or 155, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95.

159. The method of claims 153 or 155, wherein the core promoter is a sequence of SEQ ID NO: 95. -276- ^{Docket No. 421688-718021 (718WO1)}

160. The method of any one of claims 152-159, wherein the recombinant polynucleotide of any one of claims 1-113, or the recombinant polynucleotide is in the plasmid of claim 114 or claim 115 or in the engineered viral vector of any one of claims 116-123.

161. The method of any one of claims 152-160, wherein the composition is the pharmaceutical composition of claim 124.

162. The method of any one of claims 152-161, wherein the target tissue is associated with the disorder.

163. The method of any one of claims 152-162, wherein the disorder is a central nervous system disorder.

164. The method of claim 163, wherein the central nervous system disorder is a neuronal disorder.

165. The method of claim 163 or claim 164, wherein the central nervous system disorder is a genetic disorder.

166. The method of any one of claims 162-165, wherein the disorder is Rett syndrome, MECP2 duplication syndrome, frontotemporal dementia, neuronal ceroid lipofuscinosis, Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson’s disease.

167. The method of any one of claims 162-165, wherein the disorder is frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease, Parkinson’s Disease, stroke, Gaucher disease, arthritis, limbic-predominant age-related transactivation response DNA-binding protein 43 (TDP-43) encephalopathy, autism, neuronal ceroid lipofuscinosis (e.g., type 11 (CLN11)), dementia, and neurodegeneration; optionally, wherein the neuronal ceroid lipofuscinosis is type 11; optionally, wherein neurodegeneration is neurodegeneration associated with normal aging.

168. The method of any one of claims 162-165, wherein the disorder is frontotemporal dementia.

169. The method of any one of claims 162-165, wherein the disorder is any one of the disorders provided in TABLE 3.

170. The method of any one of claims 152-169, wherein the therapeutic sequence encodes a therapeutic protein. -277- ^{Docket No. 421688-718021 (718WO1)}

171. The method of claim 170, wherein the therapeutic protein is a neuronal protein or an antibody.

172. The method of claim 170 or claim 171, wherein the therapeutic protein is associated with a central nervous system disorder.

173. The method of claim 172, wherein the central nervous system disorder is a neuronal disorder.

174. The method of claim 172 or claim 173, wherein the central nervous system disorder is a genetic disorder.

175. The method of any one of claims 170-174, wherein the therapeutic protein is MECP2 or progranulin.

176. The method of any one of claims 170-175, wherein the therapeutic protein is encoded by a gene provided in TABLE 3.

177. The method of any one of claims 125-176, wherein the payload encodes a therapeutic polynucleotide.

178. The method of claim 177, wherein the therapeutic polynucleotide is a guide RNA or a suppressor tRNA.

179. The method of claim 1177 or claim 178, wherein the therapeutic polynucleotide targets a gene provided in TABLE 3.

180. A method of treating frontotemporal dementia in a subject having frontotemporal dementia, the method comprising: delivering a recombinant polynucleotide comprising an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof, and a coding sequence operably linked to the enhancer, to the subject having frontotemporal dementia; and expressing a progranulin encoded by the coding sequence, thereby treating the subject.

181. A method of treating frontotemporal dementia in a subject having frontotemporal dementia, the method comprising: delivering a recombinant polynucleotide comprising an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 4, or a reverse complement thereof, a core -278- ^{Docket No. 421688-718021 (718WO1)} promoter, and a coding sequence operably linked to the enhancer and the core promoter, to the subject having frontotemporal dementia; and expressing a progranulin encoded by the coding sequence, thereby treating the subject.

182. A method of treating frontotemporal dementia in a subject having frontotemporal dementia, the method comprising: delivering the recombinant polynucleotide of any one of claims 1-113, the recombinant polynucleotide in the plasmid of claim 114 or claim 115 or in the viral vector of any one of claims 116-123, or the pharmaceutical composition of claim 124 to the subject having frontotemporal dementia, thereby treating the frontotemporal dementia.

183. The method of any one of claims 180-182, wherein the enhancer is a sequence of SEQ ID NO: 4.

184. The method of claims 181, wherein the core promoter comprises a TATA box, an RNA polymerase binding sequence, a B recognition element, a CCAAT box, a Pribnow box, a YB_TATA promoter, or a combination thereof.

185. The method of claims 181, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to any one of SEQ ID NO: 81 – SEQ ID NO: 236 or SEQ ID NO: 363 – SEQ ID NO: 366.

186. The method of claims 181, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95.

187. The method of claims 181, wherein the core promoter is a sequence of SEQ ID NO: 95.

188. The method of any one of claims 180-187, comprising expressing the progranulin in a cerebrospinal fluid of the subject.

189. The method of claim 188, wherein the progranulin is expressed in the cerebrospinal fluid at a level of not less than 10 ng/mL and not more than 100 ng/mL.

190. The method of claim 188, wherein the progranulin is expressed in the cerebrospinal fluid at a level of not less than 1 ng/mL and not more than 100 ng/mL. -279- ^{Docket No. 421688-718021 (718WO1)}

191. The method of claim 188, wherein the progranulin is expressed in the cerebrospinal fluid at a level of not less than 10 ng/mL and not more than 30 ng/mL.

192. The method of claim 188, wherein the progranulin is expressed in the cerebrospinal fluid at a level of not less than 1 ng/mL and not more than 30 ng/mL.

193. The method of claim 188, wherein the progranulin is expressed in the cerebrospinal fluid at a level of not less than 10 ng/mL and not more than 50 ng/mL.

194. The method of claim 188, wherein the progranulin is expressed in the cerebrospinal fluid at a level of not less than 10 ng/mL and not more than 30 ng/mL.

195. The method of claim 188, wherein the progranulin is expressed in the cerebrospinal fluid at a level of not less than 70 ng/mL and not more than 180 ng/mL.

196. The method of claim 188, wherein the progranulin is expressed in the cerebrospinal fluid at a level of not less than 70 ng/mL and not more than 300 ng/mL.

197. The method of any one of claims 188-196, wherein an expression level of the progranulin in a serum of the subject is not more than 100-fold, not more than 50-fold, not more than 25-fold, not more than 20-fold, or not more than 10-fold an expression level of the progranulin in the cerebrospinal fluid.

198. The method of any one of claims 188-197, wherein an expression level of the progranulin in a serum of the subject is not less than 0.01-fold, not less than 0.05-fold, not less than 0.1-fold, not less than 0.2-fold, not less than 0.25-fold, or not less than 0.5-fold an expression level of the progranulin in the cerebrospinal fluid.

199. The method of any one of claims 188-198, wherein an expression level of the progranulin in a serum of the subject is not more than 300 ng/mL.

200. The method of any one of claims 188-198, wherein an expression level of the progranulin in a serum of the subject is not more than 1500 ng/mL.

201. The method of any one of claims 125-200, wherein the subject is a mammal.

202. The method of claim 201, wherein the mammal is a human, a non-human primate, a rat, a rabbit, a mouse, or a guinea pig. -280- ^{Docket No. 421688-718021 (718WO1)}

203. The method of any one of claims 125-202, wherein the delivering comprises intravenous administration.

204. The method of any one of claims 125-203, wherein the core promoter is capable of binding to a polymerase.

205. A recombinant polynucleotide comprising a promoter, wherein the promoter comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof; and a core promoter.

206. The recombinant polynucleotide of claim 205, wherein the enhancer comprises a sequence having at least 90% sequence identity to SEQ ID NO: 362, or a reverse complement thereof.

207. The recombinant polynucleotide of claim 205, wherein the enhancer comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 362, or a reverse complement thereof.

208. The recombinant polynucleotide of any one of claims 205-207, further comprising a payload, wherein: the payload is under transcriptional control of the promoter, and the payload comprises a coding sequence encoding a protein.

209. The recombinant polynucleotide of claim 208, wherein the promoter enhances the transcription of the payload in a target tissue.

210. The recombinant polynucleotide of claim 209, wherein the target tissue is liver tissue.

211. The recombinant polynucleotide of any one of claims 205-210, wherein the core promoter comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to SEQ ID NO: 95.

212. The recombinant polynucleotide of any one of claims 208-211, wherein the payload encodes a protein; optionally, wherein the protein is a therapeutic protein.

213. The recombinant polynucleotide of claim 212, wherein the protein is a liver protein or an antibody; optionally, wherein the antibody is a therapeutic antibody. -281- ^{Docket No. 421688-718021 (718WO1)}

214. The recombinant polynucleotide of claim 212 or claim 213, wherein the protein is associated with a liver disorder.

215. A method of expressing a payload in a target cell or a target tissue in a subject, the method comprising: delivering a recombinant polynucleotide to the target cell or the target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof, and a payload operably linked to the enhancer; and transcribing the payload in the target cell or the target tissue.

216. A method of treating a disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising a recombinant polynucleotide to a target cell or a target tissue in a subject, wherein the recombinant polynucleotide comprises: an enhancer comprising a sequence having at least 80% sequence identity to SEQ ID NO: 362, or a reverse complement thereof, and a payload operably linked to the enhancer; and expressing a therapeutic sequence encoded by the payload in the target cell or the target tissue of the subject, thereby treating the disorder.

217. The method of claim 215 or claim 216, wherein the disorder is a liver disorder.

218. The method of claim 216 or claim 217, wherein the therapeutic sequence encodes a therapeutic protein. -282- ^{Docket No. 421688-718021 (718WO1)}