CN117120613A - 用于调节pnpla3表达的组合物和方法 - Google Patents
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| PCT/US2022/024657 WO2022221430A1 (en) | 2021-04-14 | 2022-04-13 | Compositions and methods for modulating pnpla3 expression |
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| WO2024112865A1 (en) | 2022-11-23 | 2024-05-30 | Eli Lilly And Company | Method of synthesizing 4'-phosphate analog nucleotide phosphoramidite |
| KR20250099265A (ko) | 2022-11-23 | 2025-07-01 | 일라이 릴리 앤드 캄파니 | 표적화 리간드-접합된 뉴클레오티드 포스포르아미다이트의 합성 방법 |
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| US5977343A (en) | 1992-05-14 | 1999-11-02 | Ribozyme Pharmaceuticals, Inc. | Synthesis, deprotection, analysis and purification of RNA and ribozymes |
| US5804683A (en) | 1992-05-14 | 1998-09-08 | Ribozyme Pharmaceuticals, Inc. | Deprotection of RNA with alkylamine |
| ATE227342T1 (de) | 1993-09-02 | 2002-11-15 | Ribozyme Pharm Inc | Enzymatische nukleiksaüre die nicht-nukleotide enthaltet |
| US5889136A (en) | 1995-06-09 | 1999-03-30 | The Regents Of The University Of Colorado | Orthoester protecting groups in RNA synthesis |
| US5998203A (en) | 1996-04-16 | 1999-12-07 | Ribozyme Pharmaceuticals, Inc. | Enzymatic nucleic acids containing 5'-and/or 3'-cap structures |
| US6111086A (en) | 1998-02-27 | 2000-08-29 | Scaringe; Stephen A. | Orthoester protecting groups |
| ES2336887T5 (es) | 2000-03-30 | 2019-03-06 | Whitehead Inst Biomedical Res | Mediadores de interferencia por ARN específicos de secuencias de ARN |
| CA2429814C (en) | 2000-12-01 | 2014-02-18 | Thomas Tuschl | Rna interference mediating small rna molecules |
| US20050159378A1 (en) | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of Myc and/or Myb gene expression using short interfering nucleic acid (siNA) |
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| WO2003040395A2 (en) | 2001-11-07 | 2003-05-15 | Applera Corporation | Universal nucleotides for nucleic acid analysis |
| US20070265220A1 (en) | 2004-03-15 | 2007-11-15 | City Of Hope | Methods and compositions for the specific inhibition of gene expression by double-stranded RNA |
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| DK2341943T3 (en) | 2008-09-22 | 2019-02-25 | Dicerna Pharmaceuticals Inc | COMPOSITIONS AND METHODS OF SPECIFIC INHIBITION OF DSRNA REPRINT WITH MODIFICATIONS |
| US8691971B2 (en) | 2008-09-23 | 2014-04-08 | Scott G. Petersen | Self delivering bio-labile phosphate protected pro-oligos for oligonucleotide based therapeutics and mediating RNA interference |
| KR101728655B1 (ko) | 2008-12-18 | 2017-04-19 | 다이서나 파마수이티컬, 인크. | 유전자 발현의 특이적 억제를 위한 연장된 다이서 기질 제제 및 방법 |
| US20100249214A1 (en) | 2009-02-11 | 2010-09-30 | Dicerna Pharmaceuticals | Multiplex dicer substrate rna interference molecules having joining sequences |
| WO2011005860A2 (en) | 2009-07-07 | 2011-01-13 | Alnylam Pharmaceuticals, Inc. | 5' phosphate mimics |
| WO2011133871A2 (en) | 2010-04-22 | 2011-10-27 | Alnylam Pharmaceuticals, Inc. | 5'-end derivatives |
| AU2012328680A1 (en) | 2011-10-25 | 2014-05-01 | Ionis Pharmaceuticals, Inc. | Antisense modulation of GCCR expression |
| EP2928877B1 (en) | 2012-12-06 | 2020-01-22 | Merck Sharp & Dohme Corp. | Disulfide masked prodrug compositions and methods |
| DK2992098T3 (da) | 2013-05-01 | 2019-06-17 | Ionis Pharmaceuticals Inc | Sammensætninger og fremgangsmåder til modulering af hbv- og ttr-ekspression |
| US10150965B2 (en) | 2013-12-06 | 2018-12-11 | Dicerna Pharmaceuticals, Inc. | Methods and compositions for the specific inhibition of transthyretin (TTR) by double-stranded RNA |
| CA2950960A1 (en) | 2014-06-06 | 2015-12-10 | Solstice Biologics, Ltd. | Polynucleotide constructs having bioreversible and non-bioreversible groups |
| DK3569711T3 (da) | 2014-12-15 | 2021-02-22 | Dicerna Pharmaceuticals Inc | Ligandmodificerede dobbeltstrengede nukleinsyrer |
| CA2976445A1 (en) * | 2015-02-13 | 2016-08-18 | Alnylam Pharmaceuticals, Inc. | Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof |
| JP7249080B2 (ja) | 2016-08-23 | 2023-03-30 | ディセルナ ファーマシューティカルズ インコーポレイテッド | 可逆的に修飾されたオリゴヌクレオチドを含む組成物及びその使用 |
| HUE059718T2 (hu) | 2016-09-02 | 2022-12-28 | Dicerna Pharmaceuticals Inc | 4'-foszfát analógok és azokat tartalmazó oligonukleotidok |
| CA3065523A1 (en) | 2017-06-02 | 2018-12-06 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods of use thereof |
| IL271680B (en) * | 2017-06-29 | 2022-09-01 | Dicerna Pharmaceuticals Inc | Compositions and methods for inhibiting hmgb1 expression |
| UY38003A (es) | 2017-12-12 | 2019-06-28 | Amgen Inc | Construcciones de arni para inhibir la expresión de pnpla3 y métodos de uso de las mismas |
| TW202542311A (zh) | 2018-09-19 | 2025-11-01 | 美商Ionis製藥公司 | Pnpla3表現之調節劑 |
| CR20210371A (es) * | 2018-12-10 | 2021-08-27 | Amgen Inc | Constructos de arni para inhibir la expresión de pnpla3 |
| AU2020358016A1 (en) * | 2019-10-02 | 2022-04-21 | Dicerna Pharmaceuticals, Inc. | Chemical modifications of small interfering RNA with minimal fluorine content |
| CA3209418A1 (en) | 2021-04-14 | 2022-10-20 | Utsav SAXENA | Compositions and methods for modulating pnpla3 expression |
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2022
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- 2022-04-13 WO PCT/US2022/024657 patent/WO2022221430A1/en not_active Ceased
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| US12084662B2 (en) | 2024-09-10 |
| EP4323519A1 (en) | 2024-02-21 |
| CA3209418A1 (en) | 2022-10-20 |
| US20220364098A1 (en) | 2022-11-17 |
| TW202500748A (zh) | 2025-01-01 |
| US20240401059A1 (en) | 2024-12-05 |
| TWI857290B (zh) | 2024-10-01 |
| KR20230171431A (ko) | 2023-12-20 |
| BR112023021109A2 (pt) | 2023-12-12 |
| TW202300645A (zh) | 2023-01-01 |
| IL307625A (en) | 2023-12-01 |
| JP2024514880A (ja) | 2024-04-03 |
| WO2022221430A1 (en) | 2022-10-20 |
| AR125351A1 (es) | 2023-07-12 |
| MX2023012216A (es) | 2023-10-26 |
| AU2022258459A1 (en) | 2023-09-14 |
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