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WO1991018913A1 - Inversion a mediation ribozymique de transformation par clivage de l'arn oncogene hras - Google Patents

Inversion a mediation ribozymique de transformation par clivage de l'arn oncogene hras Download PDF

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Publication number
WO1991018913A1
WO1991018913A1 PCT/US1990/003218 US9003218W WO9118913A1 WO 1991018913 A1 WO1991018913 A1 WO 1991018913A1 US 9003218 W US9003218 W US 9003218W WO 9118913 A1 WO9118913 A1 WO 9118913A1
Authority
WO
WIPO (PCT)
Prior art keywords
ribozyme
plasmid
hras
rna
cleavage
Prior art date
Application number
PCT/US1990/003218
Other languages
English (en)
Inventor
Kevin J. Scanlon
Original Assignee
City Of Hope
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by City Of Hope filed Critical City Of Hope
Priority to PCT/US1990/003218 priority Critical patent/WO1991018913A1/fr
Priority to PCT/US1990/006226 priority patent/WO1991018624A1/fr
Priority to AU88799/91A priority patent/AU8879991A/en
Priority to AU71521/91A priority patent/AU7152191A/en
Priority to PCT/US1990/007459 priority patent/WO1991018625A1/fr
Publication of WO1991018913A1 publication Critical patent/WO1991018913A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C12N2310/111—Antisense spanning the whole gene, or a large part of it
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/12—Type of nucleic acid catalytic nucleic acids, e.g. ribozymes
    • C12N2310/121—Hammerhead

Definitions

  • This invention relates to a ribozyme effective to cleave oncogene RNA. More particularly the invention relates to a ribozyme effective to cleave Hras RNA at a GUC site on codon 12 where an activating point mutation may appear, to a plasmid into which said ribozyme has been cloned, to mammalian cells into which said plasmid has been transfected and which express said ribozyme and to cancer therapy which entails the administration of such ribozymes per se are of such plasmids to induce jLn vivo expression of such ribozymes.
  • These ribozyme plasmids can reverse the transformation process back to the normal cell phenotype.
  • Ribozyme cleavage of various RNA transcripts is known. See, e.g., published PCT applications no. 89/05852 and no. 88/04300 and pending U.S. Application 9/401,613 filed August 31, 1989.
  • RNA does not include a ribozyme cleavage site on codon 12.
  • the point mutation which yields a malignancy inducing Hras transcript does include such a cleavage site.
  • This invention provides a ribozyme effective to cleave the mutated gene but not the normal gene.
  • the ribozyme of the invention is effective to cleave the mutated gene both in vitro and in vivo. It accordingly provides unique therapy for bladder carcinoma and other malignancies which may be induced by cells transformed by the mutated Hras gene product.
  • the ribozyme of the invention may be administered by a known delivery system such as a liposome or by other means known to the art. It may also be administered in the form of a vector (i.e., RNA tumor virus) into which it has been cloned and which will express the ribozyme.
  • the invention also includes a ribozyme which inhibits C-fos expression in response to cis-platin or other stimuli.
  • the Hras RNA included in mutated gene transcript includes a GUC site appropriate for ribozyme cleavage as shown in II.
  • the ribozyme per se may be synthesized in known manner by use of a commercially available synthesizer produced, for example, by Applied Biosystems, Inc. or Milligen.
  • This molecule is then cloned into a plasmid capable of synthesizing the ribozyme _in vivo when transfected into a mammalian cell.
  • Appropriate promoters and terminal sequences may preside and follow the • • ribozyme" component of the DNA insert to be cloned into the plasmid.
  • appropriate nucleotide sequences having sufficient overlapping base pairs are amplified by the poly erase chain reaction to provide the insert to be cloned.
  • the 3' and 5' terminus include restriction sites to insure the correct positioning of the insert in the plasmid.
  • a T7 RNA polymerase promoter may be positioned at the 5' terminus of the "ribozyme" to accommodate in vitro cleavage.
  • One appropriate construct is shown by IV.
  • the T7 RNA polymerase promoter sequence may be omitted if in vitro cleavage of Hras RNA is not contemplated.
  • a preferred plasmid is pH-0-Apr.l which yields the corresponding vector pE- ⁇ Apr.l-Hras-R in which R is the double stranded PCR product, one strand of which is the Hras ribozyme.
  • Other plasmids useful in the invention include pH ⁇ pKoneo, the pSV2 cat plasmid and pMAMneo.
  • the DNA fragments are cloned by sticky end ligation into a selected site of the plasmid.
  • the Hras ribozymes or the plasmid vectors which express such ribozymes of the invention may be administered by injection of appropriate delivery systems such as lipomes.
  • one aspect of the invention includes liposomes in which the Hras ribozymes are encapsulated or are included in the lyposomal bilayers.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un ribozyme efficace pour cliver l'ARN oncogène. Elle concerne plus particulièrement un ribozyme efficace pour cliver l'ARN Hras au niveau d'un site GUC sur le codon 12 où peut apparaître une mutation ponctuelle d'activation, un plasmide dans lequel a été cloné ledit ribozyme, des cellules dans lesquelles a été transfecté ledit plasmide et qui expriment ledit ribozyme, et une thérapie du cancer qui comporte l'administration de tels ribozymes en soi et de tels plasmides pour induire l'expression in vivo de tels ribozymes. Ces plasmides ribozymiques peuvent inverser le processus de transformation en vue d'un retour au phénotype cellulaire normal.
PCT/US1990/003218 1990-06-07 1990-06-07 Inversion a mediation ribozymique de transformation par clivage de l'arn oncogene hras WO1991018913A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/US1990/003218 WO1991018913A1 (fr) 1990-06-07 1990-06-07 Inversion a mediation ribozymique de transformation par clivage de l'arn oncogene hras
PCT/US1990/006226 WO1991018624A1 (fr) 1990-06-07 1990-11-01 Inversion a mediation ribozymique de transformation par clivage de l'arn oncogene hras
AU88799/91A AU8879991A (en) 1990-06-07 1990-11-01 Ribozyme mediated reversal of transformation by cleavage of the hras oncogene rna
AU71521/91A AU7152191A (en) 1990-06-07 1990-12-19 Ribozyme mediated reversal of transformation by cleavage of the hras oncogene rna
PCT/US1990/007459 WO1991018625A1 (fr) 1990-06-07 1990-12-19 Inversion a mediation ribozymique de transformation par clivage de l'arn oncogene hras

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1990/003218 WO1991018913A1 (fr) 1990-06-07 1990-06-07 Inversion a mediation ribozymique de transformation par clivage de l'arn oncogene hras

Publications (1)

Publication Number Publication Date
WO1991018913A1 true WO1991018913A1 (fr) 1991-12-12

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PCT/US1990/003218 WO1991018913A1 (fr) 1990-06-07 1990-06-07 Inversion a mediation ribozymique de transformation par clivage de l'arn oncogene hras
PCT/US1990/006226 WO1991018624A1 (fr) 1990-06-07 1990-11-01 Inversion a mediation ribozymique de transformation par clivage de l'arn oncogene hras

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AU (1) AU8879991A (fr)
WO (2) WO1991018913A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5246921A (en) * 1990-06-26 1993-09-21 The Wistar Institute Of Anatomy And Biology Method for treating leukemias
US5496698A (en) * 1992-08-26 1996-03-05 Ribozyme Pharmaceuticals, Inc. Method of isolating ribozyme targets
US5599704A (en) * 1992-08-26 1997-02-04 Ribozyme Pharmaceuticals, Inc. ErbB2/neu targeted ribozymes
US5610052A (en) * 1992-08-26 1997-03-11 Ribozyme Pharmaceuticals Inc. Enzymatic RNA with activity to ras
US5612215A (en) * 1992-12-07 1997-03-18 Ribozyme Pharmaceuticals, Inc. Stromelysin targeted ribozymes
US5616490A (en) * 1992-12-07 1997-04-01 Ribozyme Pharmaceuticals, Inc. Ribozymes targeted to TNF-α RNA
US5616488A (en) * 1992-12-07 1997-04-01 Ribozyme Pharmaceuticals, Inc. IL-5 targeted ribozymes
US5631360A (en) * 1992-05-14 1997-05-20 Ribozyme Pharmaceuticals, Inc. N-phthaloyl-protected 2'-amino-nucleoside phosphoramdites
US5639655A (en) * 1993-01-19 1997-06-17 Ribozyme Pharmaceuticals, Inc. PML-RARA targeted ribozymes
US5646042A (en) * 1992-08-26 1997-07-08 Ribozyme Pharmaceuticals, Inc. C-myb targeted ribozymes
US5658780A (en) * 1992-12-07 1997-08-19 Ribozyme Pharmaceuticals, Inc. Rel a targeted ribozymes
US5686599A (en) * 1992-05-14 1997-11-11 Ribozyme Pharmaceuticals, Inc. Synthesis, deprotection, analysis and purification of RNA and ribozymes
EP0808898A1 (fr) * 1996-05-24 1997-11-26 Hoechst Aktiengesellschaft Réactif et Procédé pour l'inhibition de l'expression du N-RAS
US5714383A (en) * 1992-05-14 1998-02-03 Ribozyme Pharmaceuticals, Inc. Method and reagent for treating chronic myelogenous leukemia
US5750390A (en) * 1992-08-26 1998-05-12 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of diseases caused by expression of the bcl-2 gene
US5804683A (en) * 1992-05-14 1998-09-08 Ribozyme Pharmaceuticals, Inc. Deprotection of RNA with alkylamine
US5811300A (en) * 1992-12-07 1998-09-22 Ribozyme Pharmaceuticals, Inc. TNF-α ribozymes
US5989906A (en) * 1992-05-14 1999-11-23 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting P-glycoprotein (mdr-1-gene)
US6080851A (en) * 1992-12-04 2000-06-27 American Home Products Corporation Ribozymes with linked anchor sequences
US6132967A (en) * 1992-12-07 2000-10-17 Ribozyme Pharmaceuticals, Inc. Ribozyme treatment of diseases or conditions related to levels of intercellular adhesion molecule-1 (ICAM-1)
US6437117B1 (en) 1992-05-14 2002-08-20 Ribozyme Pharmaceuticals, Inc. Synthesis, deprotection, analysis and purification for RNA and ribozymes
US6492512B1 (en) 1992-08-26 2002-12-10 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of lung cancer and other malignancies caused by the deregulation of L-MYC gene expression
US6544755B1 (en) 1992-08-26 2003-04-08 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of diseases by expression of the c-Myc gene
US6656731B1 (en) 1997-09-22 2003-12-02 Max Planck Gesellschaft Zur Forderung Der Wissenschaften E.V. Nucleic acid catalysts with endonuclease activity

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023057A1 (fr) * 1992-05-14 1993-11-25 Ribozyme Pharmaceuticals, Inc. Procede et reactif destines a empecher l'evolution du cancer
US6103890A (en) * 1994-05-18 2000-08-15 Ribozyme Pharmaceuticals, Inc. Enzymatic nucleic acids that cleave C-fos
IL318625A (en) 2022-07-29 2025-03-01 Regeneron Pharma Compositions and methods for transferrin receptor (TFR)-mediated delivery to brain and muscle
US20240182561A1 (en) 2022-11-04 2024-06-06 Regeneron Pharmaceuticals, Inc. Calcium voltage-gated channel auxiliary subunit gamma 1 (cacng1) binding proteins and cacng1-mediated delivery to skeletal muscle
WO2024107765A2 (fr) 2022-11-14 2024-05-23 Regeneron Pharmaceuticals, Inc. Compositions et procédés d'administration médiée par le récepteur 3 du facteur de croissance des fibroblastes à des astrocytes

Citations (2)

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WO1988004300A1 (fr) * 1986-12-03 1988-06-16 University Patents, Inc. Polymerases de ribozyme d'arn, dephosphorylases endoribonucleases de restriction et procedes
EP0321201A2 (fr) * 1987-12-15 1989-06-21 Gene Shears Pty. Limited Ribozymes

Patent Citations (2)

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WO1988004300A1 (fr) * 1986-12-03 1988-06-16 University Patents, Inc. Polymerases de ribozyme d'arn, dephosphorylases endoribonucleases de restriction et procedes
EP0321201A2 (fr) * 1987-12-15 1989-06-21 Gene Shears Pty. Limited Ribozymes

Non-Patent Citations (6)

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Title
CHEMICAL ABSTRACTS, Volume 110, No. 21, issued 22 May 1990, (Columbus, Ohio, U.S.A.), T.R. CECH et al., "RNA Ribozyme Polymerases, Dephosphorylases, Restriction Endoribonucleases and Methods for Their Manufacture", page 226, Abstract No. 187321K; & WO,A,88 04300, 16 June 1988. *
CHEMICAL ABSTRACTS, Volume 112, No. 19, issued 07 May 1990, (Columbus, Ohio, U.S.A.), N. SARVER et al., "Ribozymes an Potential Anti-HIV-1 Therapeutic Agents", page 420, Abstract No. 175480q; & SCIENCE, 1990, 247(u9u7), 1222-5, (ENG). *
CHEMICAL ABSTRACTS, Volume 112, No. 7, issued 12 February 1990, (Columbus, Ohio U.S.A.), W. GERLACH et al., "Synthetic Ribozymes for In Vivo Inactivation of Prokaryotic or Eukaryotic RNA Transcripts", pages 336-337, Abstract No. 51284; & EP,A,321 201, 21 June 1989. *
CHEMICAL ABSTRACTS, Volume 112, No. 7, issued 12 February 1990, (Columbus, Ohio, U.S.A.), M. COTTEN et al., "Ribozyme Mediated Destruction of RNA In Vivo", page 501, Abstract No. 52942; & EMBO J., 1990, 8(12), 3861-6, (ENG). *
NATURE, Volume 344, issued 05 April 1990, J. PENEAULT et al., "Mixed Deoxyribo-and Riboligo-Nucleotides with Catalytic Activity", pages 565-567. *
PROC. NATL. ACAD. SCI. U.S.A., Volume 86, No. 23, issued December 1989, (U.S.A.), F.H. CAMERON et al., "Specific Gene Suppression by Engineered Ribozymes in Monkey Cells", pages 9139-9143. *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5246921A (en) * 1990-06-26 1993-09-21 The Wistar Institute Of Anatomy And Biology Method for treating leukemias
US6469158B1 (en) 1992-05-14 2002-10-22 Ribozyme Pharmaceuticals, Incorporated Synthesis, deprotection, analysis and purification of RNA and ribozymes
US6437117B1 (en) 1992-05-14 2002-08-20 Ribozyme Pharmaceuticals, Inc. Synthesis, deprotection, analysis and purification for RNA and ribozymes
US5989906A (en) * 1992-05-14 1999-11-23 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting P-glycoprotein (mdr-1-gene)
US7041817B2 (en) 1992-05-14 2006-05-09 Sirna Therapeutics, Inc. Synthesis, deprotection, analysis and purification of RNA and ribozymes
US6649751B2 (en) 1992-05-14 2003-11-18 Sirna Therapeutics, Inc. Synthesis, deprotection, analysis and purification of RNA and ribozymes
US5831071A (en) * 1992-05-14 1998-11-03 Ribozyme Pharmaceuticals, Inc. Synthesis deprotection analysis and purification of RNA and ribozymes
US5631360A (en) * 1992-05-14 1997-05-20 Ribozyme Pharmaceuticals, Inc. N-phthaloyl-protected 2'-amino-nucleoside phosphoramdites
US5804683A (en) * 1992-05-14 1998-09-08 Ribozyme Pharmaceuticals, Inc. Deprotection of RNA with alkylamine
US6353098B1 (en) 1992-05-14 2002-03-05 Ribozyme Pharmaceuticals, Inc. Synthesis, deprotection, analysis and purification of RNA and ribozymes
US5686599A (en) * 1992-05-14 1997-11-11 Ribozyme Pharmaceuticals, Inc. Synthesis, deprotection, analysis and purification of RNA and ribozymes
US5714383A (en) * 1992-05-14 1998-02-03 Ribozyme Pharmaceuticals, Inc. Method and reagent for treating chronic myelogenous leukemia
US5599704A (en) * 1992-08-26 1997-02-04 Ribozyme Pharmaceuticals, Inc. ErbB2/neu targeted ribozymes
US5646042A (en) * 1992-08-26 1997-07-08 Ribozyme Pharmaceuticals, Inc. C-myb targeted ribozymes
US5750390A (en) * 1992-08-26 1998-05-12 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of diseases caused by expression of the bcl-2 gene
US5801158A (en) * 1992-08-26 1998-09-01 Ribozyme Pharmaceuticals, Inc. Enzymatic RNA with activity to RAS
US6492512B1 (en) 1992-08-26 2002-12-10 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of lung cancer and other malignancies caused by the deregulation of L-MYC gene expression
US5496698A (en) * 1992-08-26 1996-03-05 Ribozyme Pharmaceuticals, Inc. Method of isolating ribozyme targets
US5817796A (en) * 1992-08-26 1998-10-06 Stinchcomb; Dan T. C-myb ribozymes having 2'-5'-linked adenylate residues
US6544755B1 (en) 1992-08-26 2003-04-08 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of diseases by expression of the c-Myc gene
US5610052A (en) * 1992-08-26 1997-03-11 Ribozyme Pharmaceuticals Inc. Enzymatic RNA with activity to ras
US6080851A (en) * 1992-12-04 2000-06-27 American Home Products Corporation Ribozymes with linked anchor sequences
US6132967A (en) * 1992-12-07 2000-10-17 Ribozyme Pharmaceuticals, Inc. Ribozyme treatment of diseases or conditions related to levels of intercellular adhesion molecule-1 (ICAM-1)
US5811300A (en) * 1992-12-07 1998-09-22 Ribozyme Pharmaceuticals, Inc. TNF-α ribozymes
US5731295A (en) * 1992-12-07 1998-03-24 Ribozyme Pharmaceuticals, Inc. Method of reducing stromelysin RNA via ribozymes
US6410224B1 (en) 1992-12-07 2002-06-25 Ribozyme Pharmaceuticals, Inc. Ribozyme treatment of diseases or conditions related to levels of NF-κB
US6436644B1 (en) 1992-12-07 2002-08-20 Ribozyme Pharmaceuticals, Inc. Ribozyme treatment of diseases or conditions related to levels of intercellular adhesion molecule-1 (CAM-1)
US5658780A (en) * 1992-12-07 1997-08-19 Ribozyme Pharmaceuticals, Inc. Rel a targeted ribozymes
US5616488A (en) * 1992-12-07 1997-04-01 Ribozyme Pharmaceuticals, Inc. IL-5 targeted ribozymes
US5616490A (en) * 1992-12-07 1997-04-01 Ribozyme Pharmaceuticals, Inc. Ribozymes targeted to TNF-α RNA
US5612215A (en) * 1992-12-07 1997-03-18 Ribozyme Pharmaceuticals, Inc. Stromelysin targeted ribozymes
US5639655A (en) * 1993-01-19 1997-06-17 Ribozyme Pharmaceuticals, Inc. PML-RARA targeted ribozymes
US6037463A (en) * 1996-05-24 2000-03-14 Hoechst Aktiengesellschaft Enzymatic RNA molecules that cleave mutant N-RAS
EP0808898A1 (fr) * 1996-05-24 1997-11-26 Hoechst Aktiengesellschaft Réactif et Procédé pour l'inhibition de l'expression du N-RAS
US6656731B1 (en) 1997-09-22 2003-12-02 Max Planck Gesellschaft Zur Forderung Der Wissenschaften E.V. Nucleic acid catalysts with endonuclease activity

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AU8879991A (en) 1991-12-31

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