WO2019000149A1 - Arnsi du gène humain codant pour le ligand de mort cellulaire programmée 1 et son utilisation - Google Patents
Arnsi du gène humain codant pour le ligand de mort cellulaire programmée 1 et son utilisation Download PDFInfo
- Publication number
- WO2019000149A1 WO2019000149A1 PCT/CN2017/089929 CN2017089929W WO2019000149A1 WO 2019000149 A1 WO2019000149 A1 WO 2019000149A1 CN 2017089929 W CN2017089929 W CN 2017089929W WO 2019000149 A1 WO2019000149 A1 WO 2019000149A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gene
- sirna
- sequence
- ligand
- programmed death
- Prior art date
Links
- 108020004459 Small interfering RNA Proteins 0.000 title description 10
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 title description 6
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 18
- 230000014509 gene expression Effects 0.000 claims abstract description 12
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 claims abstract description 7
- 230000009368 gene silencing by RNA Effects 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 4
- 239000012634 fragment Substances 0.000 claims abstract 4
- 230000002159 abnormal effect Effects 0.000 claims abstract 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 3
- 230000000692 anti-sense effect Effects 0.000 claims description 3
- 229940079593 drug Drugs 0.000 abstract 1
- 102000008096 B7-H1 Antigen Human genes 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 239000004055 small Interfering RNA Substances 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 238000003753 real-time PCR Methods 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 230000000139 costimulatory effect Effects 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 238000002123 RNA extraction Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 108091081021 Sense strand Proteins 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Definitions
- the present invention belongs to the field of molecular genetics, and more particularly to a siRN capable of inhibiting human programmed death ligand 1
- Non-small cell lung cancer is a common malignant tumor in the world, and its incidence is increasing year by year. Studying NSCLC tumor recurrence factors and tumor immune escape mechanisms has important theoretical significance and clinical application value. T lymphocytes are important effector cells that mediate tumor immune responses, and T cell activation requires TCR-mediated antigen-specific signaling and costimulatory molecule-mediated costimulatory signals.
- PD-L1 Programmed death ligand 1
- B7-H1 is a negative T cell costimulatory molecule in the B7 family
- PD-L1 inhibits proliferation of CD4 and CD8 T cells by binding to its receptor PD-1
- activation negative regulation of the body's immune response process, thereby mediating tumor immune escape, and promoting tumor growth
- the vector that inhibits the expression of the PD-L1 gene makes the related research not well developed.
- RNA interference RNA interference
- RNAi small interfering RNA
- siPDL1 sequence is as follows: [0007] Justice Chain: 5,- GCCGAAGUCAUCUGGACAA-3' (SEQ ID NO: 1)
- Antisense strand 5,- UUGUCCAGAUGACUUCGGC-3' (SEQ ID NO: 2).
- the siPDL1 provided by the present invention has the advantages of high interference efficiency, high and specific inhibition of PD-L1 gene expression, and can be used as a powerful tool for preparing a medicament for treating a PD-L1 gene expression-related disease. Brief description of the drawing
- FIG. 1 is a schematic diagram showing the results of quantitative PCR detection of PD-L1 gene expression levels after HepG2 cells transfected with siPDL1.
- HepG2 cells purchased from ATCC
- cultured in DMEM complete medium containing 10% fetal bovine serum
- plated 6-well plates at a ratio of 150,000 cells/well, and cultured at 37 ° C, 5% CO 2 for 18 h.
- Cell transfection was performed using the Lipofectamine 3000 Transfection Kit (Invitrogen) according to the product instructions.
- Transfected sputum, transfected A375 cells with lOO pmol siPDL1 the ratio of siRNA to liposome was 100 pmol: 10 ⁇ .
- Total RNA extraction Total RNA of PD-L1 cells normal and transfected with siPDL1 was extracted using the QIAGEN RNeasy Mini Kit.
- Reverse Transcription Reverse transcription was performed using FastQuant RT Super Mix.
- the siPDL1 provided by the present invention has the advantages of high interference efficiency, high and specific inhibition of PD-L1 gene expression, and can be used as a powerful tool for preparing a medicament for treating a PD-L1 gene expression-related disease.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Biotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- General Engineering & Computer Science (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
L'invention concerne un fragment d'ARN interférent et son utilisation dans la préparation d'un médicament destiné au traitement d'une maladie associée à l'expression anormale du gène PD-L1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2017/089929 WO2019000149A1 (fr) | 2017-06-26 | 2017-06-26 | Arnsi du gène humain codant pour le ligand de mort cellulaire programmée 1 et son utilisation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2017/089929 WO2019000149A1 (fr) | 2017-06-26 | 2017-06-26 | Arnsi du gène humain codant pour le ligand de mort cellulaire programmée 1 et son utilisation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2019000149A1 true WO2019000149A1 (fr) | 2019-01-03 |
Family
ID=64741975
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2017/089929 WO2019000149A1 (fr) | 2017-06-26 | 2017-06-26 | Arnsi du gène humain codant pour le ligand de mort cellulaire programmée 1 et son utilisation |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2019000149A1 (fr) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007084865A2 (fr) * | 2006-01-13 | 2007-07-26 | Sirna Therapeutics, Inc. | INHIBITION DE L’EXPRESSION DU GENE B7-H1 MEDIEE PAR UNE INTERFERENCE DE L’ARN EN UTILISANT UN ACIDE NUCLEIQUE INTERFERANT COURT (NAsi) |
| WO2017040078A1 (fr) * | 2015-09-02 | 2017-03-09 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni ciblant le ligand de mort cellulaire programmée 1 (pd-l1) et leurs méthodes d'utilisation |
-
2017
- 2017-06-26 WO PCT/CN2017/089929 patent/WO2019000149A1/fr active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007084865A2 (fr) * | 2006-01-13 | 2007-07-26 | Sirna Therapeutics, Inc. | INHIBITION DE L’EXPRESSION DU GENE B7-H1 MEDIEE PAR UNE INTERFERENCE DE L’ARN EN UTILISANT UN ACIDE NUCLEIQUE INTERFERANT COURT (NAsi) |
| WO2017040078A1 (fr) * | 2015-09-02 | 2017-03-09 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni ciblant le ligand de mort cellulaire programmée 1 (pd-l1) et leurs méthodes d'utilisation |
Non-Patent Citations (2)
| Title |
|---|
| HUANG, WENYUE: "Research on Inhibition of B7-H1 Gene Expression in Human Umbilical Cord Mesenchymal Stem Cells by RNAi Technology", CHINA DISSERTATION DATABASE, 8 November 2013 (2013-11-08) * |
| WILLEMIJN HOBO ET AL.: "SiRNA Silencing of PD-L1 and PD-L2 on Dendritic Cells Augments Expansion and Function of Minor Histocompatibility Antigen-specific CD 8+ T Cells", BLOOD. IMMUNOBIOLOGY, vol. 116, no. 22, 25 November 2010 (2010-11-25), pages 4501 - 4510, XP055558438, ISSN: 0171-2985 * |
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