JP2018518186A5 - - Google Patents
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- JP2018518186A5 JP2018518186A5 JP2017565893A JP2017565893A JP2018518186A5 JP 2018518186 A5 JP2018518186 A5 JP 2018518186A5 JP 2017565893 A JP2017565893 A JP 2017565893A JP 2017565893 A JP2017565893 A JP 2017565893A JP 2018518186 A5 JP2018518186 A5 JP 2018518186A5
- Authority
- JP
- Japan
- Prior art keywords
- thiol
- compound
- sirna
- stranded oligonucleotide
- oligonucleotide
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
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- 108091034117 Oligonucleotide Proteins 0.000 claims description 504
- 150000001875 compounds Chemical class 0.000 claims description 303
- 108020004459 Small interfering RNA Proteins 0.000 claims description 218
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 193
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- -1 thiopropionate Chemical compound 0.000 claims description 38
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- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 27
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 27
- 150000001345 alkine derivatives Chemical class 0.000 claims description 27
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- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 27
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- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 claims description 26
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 22
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- 239000010452 phosphate Substances 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- 229920003192 poly(bis maleimide) Polymers 0.000 claims description 9
- XQUPVDVFXZDTLT-UHFFFAOYSA-N 1-[4-[[4-(2,5-dioxopyrrol-1-yl)phenyl]methyl]phenyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C(C=C1)=CC=C1CC1=CC=C(N2C(C=CC2=O)=O)C=C1 XQUPVDVFXZDTLT-UHFFFAOYSA-N 0.000 claims description 7
- BSYKBLKUYLXUCJ-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethanol pyrrole-2,5-dione Chemical compound C(COCCO)O.C1(C=CC(N1)=O)=O BSYKBLKUYLXUCJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 239000001273 butane Substances 0.000 claims 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 2
- JDVPQXZIJDEHAN-UHFFFAOYSA-N succinamic acid Chemical class NC(=O)CCC(O)=O JDVPQXZIJDEHAN-UHFFFAOYSA-N 0.000 claims 2
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 22
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Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101141544B1 (ko) | 2009-03-13 | 2012-05-03 | 한국과학기술원 | 에스아이알엔에이 다중 접합체 및 이의 제조방법 |
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| IL316159A (en) | 2015-06-15 | 2024-12-01 | Mpeg La Llc | Defined Oligonucleotide Multimers and Methods for Manufacture Thereof |
| US10633653B2 (en) | 2015-08-14 | 2020-04-28 | University Of Massachusetts | Bioactive conjugates for oligonucleotide delivery |
| WO2017132669A1 (en) * | 2016-01-31 | 2017-08-03 | University Of Massachusetts | Branched oligonucleotides |
| WO2018013525A1 (en) | 2016-07-11 | 2018-01-18 | Translate Bio Ma, Inc. | Nucleic acid conjugates and uses thereof |
| WO2018013640A1 (en) | 2016-07-15 | 2018-01-18 | University Of Massachusetts | Process of delivering small rnas to sperm |
| CA3033368A1 (en) | 2016-08-12 | 2018-02-15 | University Of Massachusetts | Conjugated oligonucleotides |
| EP3576752A4 (en) * | 2017-02-06 | 2020-12-16 | Mpeg La, LLC | MULTIMERIC OLIGONUCLEOTIDES WITH REDUCED RENAL CLEARANCE |
| JP7406793B2 (ja) | 2017-06-23 | 2023-12-28 | ユニバーシティー オブ マサチューセッツ | ２テイル自己デリバリー型ｓｉＲＮＡおよび関連方法 |
| CA3075205A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | Stabilized hnf4a sarna compositions and methods of use |
| WO2019140102A1 (en) * | 2018-01-10 | 2019-07-18 | Translate Bio Ma, Inc. | Compositions and methods for facilitating delivery of synthetic nucleic acids to cells |
| CN111886231B (zh) | 2018-04-05 | 2023-08-01 | 株式会社Lg化学 | 基于咔唑的化合物和包含其的有机发光器件 |
| WO2020033899A1 (en) | 2018-08-10 | 2020-02-13 | University Of Massachusetts | Modified oligonucleotides targeting snps |
| JP7627042B2 (ja) | 2018-08-23 | 2025-02-05 | ユニバーシティー オブ マサチューセッツ | Ｏ－メチルリッチ完全安定化オリゴヌクレオチド |
| CN113164507A (zh) * | 2018-09-28 | 2021-07-23 | 圣诺制药公司 | 由多个寡核苷酸构成的通过与靶标的互补相互作用调控基因表达的多靶向核酸构建体 |
| CN113614232A (zh) | 2019-01-18 | 2021-11-05 | 马萨诸塞大学 | 动态药代动力学修饰锚 |
| CA3132505A1 (en) * | 2019-03-04 | 2020-09-10 | Mpeg La, L.L.C. | Multimeric oligonucleotides with enhanced bioactivity |
| US12478684B2 (en) * | 2019-04-11 | 2025-11-25 | Northeastern University | Oligonucleotide-polymer miktoarm conjugates and methods of use |
| AU2020319911A1 (en) * | 2019-07-30 | 2022-02-24 | Mpeg La, L.L.C. | Subcutaneous delivery of multimeric oligonucleotides with enhanced bioactivity |
| MX2022001710A (es) | 2019-08-09 | 2022-05-10 | Univ Massachusetts | Oligonucleótidos modificados químicamente dirigidos a los snp. |
| US12365894B2 (en) | 2019-09-16 | 2025-07-22 | University Of Massachusetts | Branched lipid conjugates of siRNA for specific tissue delivery |
| CN111041025B (zh) | 2019-12-17 | 2021-06-18 | 深圳市瑞吉生物科技有限公司 | 基于结合N-乙酰半乳糖胺多肽的mRNA靶向分子及其制备方法 |
| CN112111524B (zh) * | 2020-01-10 | 2024-02-27 | 深圳瑞吉生物科技有限公司 | mRNA-GalNAc靶向分子的制备方法及其体内递送系统和应用 |
| AU2021263932B2 (en) * | 2020-04-30 | 2025-07-03 | Mpeg La, L.L.C. | Multimeric oligonucleotides with divided strands |
| CA3178559A1 (en) * | 2020-05-19 | 2021-11-25 | Jonathan Miles Brown | Orthogonally linked multimeric oligonucleotides |
| WO2021242883A1 (en) | 2020-05-26 | 2021-12-02 | University Of Massachusetts | Synthetic oligonucleotides having regions of block and cluster modifications |
| CN111744019B (zh) | 2020-07-01 | 2023-08-04 | 深圳瑞吉生物科技有限公司 | 基于甘露糖的mRNA靶向递送系统及其应用 |
| US20240318174A1 (en) * | 2021-02-08 | 2024-09-26 | Ractigen Therapeutics | Multi-Valent Oligonucleotide Agent and Methods of Use Thereof |
| AU2022299169A1 (en) | 2021-06-23 | 2024-02-08 | Beth Israel Deaconess Medical Center, Inc. | Optimized anti-flt1 oligonucleotide compounds for treatment of preeclampsia and other angiogenic disorders |
| CN115010794A (zh) * | 2022-06-30 | 2022-09-06 | 武汉瑞佶生物科技有限公司 | 蛋白质介导的mRNA靶向分子及其制备方法和应用 |
| JP2025531341A (ja) * | 2022-09-19 | 2025-09-19 | カイロンノヴァ （シャーメン） バイオファーマ カンパニー，リミテッド | 炭水化物－オリゴヌクレオチド複合体、薬物組成物および治療への応用 |
| WO2024228030A2 (en) | 2023-05-04 | 2024-11-07 | Argonaute RNA Limited | Dual silencing |
Family Cites Families (55)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5034506A (en) | 1985-03-15 | 1991-07-23 | Anti-Gene Development Group | Uncharged morpholino-based polymers having achiral intersubunit linkages |
| US5714331A (en) | 1991-05-24 | 1998-02-03 | Buchardt, Deceased; Ole | Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility |
| US5719262A (en) | 1993-11-22 | 1998-02-17 | Buchardt, Deceased; Ole | Peptide nucleic acids having amino acid side chains |
| US5539082A (en) | 1993-04-26 | 1996-07-23 | Nielsen; Peter E. | Peptide nucleic acids |
| GB9207381D0 (en) | 1992-04-03 | 1992-05-13 | Ici Plc | Synthesis of oligonucleotides |
| EP1272630A2 (en) | 2000-03-16 | 2003-01-08 | Genetica, Inc. | Methods and compositions for rna interference |
| US8202846B2 (en) | 2000-03-16 | 2012-06-19 | Cold Spring Harbor Laboratory | Methods and compositions for RNA interference |
| EP2390331B1 (en) | 2001-09-28 | 2018-04-25 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | MicroRNA molecules |
| AU2003282722A1 (en) | 2002-10-02 | 2004-04-23 | Alnylam Pharmaceuticals Inc. | Therapeutic compositions |
| WO2004080406A2 (en) | 2003-03-07 | 2004-09-23 | Alnylam Pharmaceuticals | Therapeutic compositions |
| AU2004227414A1 (en) | 2003-04-03 | 2004-10-21 | Alnylam Pharmaceuticals | iRNA conjugates |
| US8969543B2 (en) | 2003-04-03 | 2015-03-03 | Bioneer Corporation | SiRNA-hydrophilic polymer conjugates for intracellular delivery of siRNA and method thereof |
| CA2521464C (en) | 2003-04-09 | 2013-02-05 | Alnylam Pharmaceuticals, Inc. | Irna conjugates |
| MXPA05011022A (es) | 2003-04-13 | 2006-04-27 | Enzon Pharmaceuticals Inc | Profarmacos oligonucleotidos polimericos. |
| JP4991288B2 (ja) | 2003-04-17 | 2012-08-01 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | 二本鎖ｉＲＮＡ剤、および二本鎖ｉＲＮＡ剤の対合の安定性を調節する方法。 |
| DK1620544T3 (en) | 2003-04-17 | 2019-01-14 | Alnylam Pharmaceuticals Inc | MODIFIED iRNA AGENTS |
| US7851615B2 (en) | 2003-04-17 | 2010-12-14 | Alnylam Pharmaceuticals, Inc. | Lipophilic conjugated iRNA agents |
| AU2005298337A1 (en) | 2004-10-25 | 2006-05-04 | Devgen Nv | RNA constructs |
| CA2857881A1 (en) | 2004-11-12 | 2006-12-28 | Asuragen, Inc. | Methods and compositions involving mirna and mirna inhibitor molecules |
| EP1989307B1 (en) * | 2006-02-08 | 2012-08-08 | Quark Pharmaceuticals, Inc. | NOVEL TANDEM siRNAS |
| EP2021008B1 (en) | 2006-04-07 | 2015-12-02 | Idera Pharmaceuticals, Inc. | Stabilized immune modulatory rna (simra) compounds for tlr7 and tlr8 |
| US20080214436A1 (en) | 2007-01-26 | 2008-09-04 | City Of Hope | Methods and compositions for the treatment of cancer or other diseases |
| US20080287383A1 (en) | 2007-03-02 | 2008-11-20 | Nastech Pharmaceutical Company Inc. | Nucleic acid compounds for inhibiting erbb gene expression and uses thereof |
| US20080311040A1 (en) * | 2007-03-06 | 2008-12-18 | Flagship Ventures | METHODS AND COMPOSITIONS FOR IMPROVED THERAPEUTIC EFFECTS WITH siRNA |
| CA2692161C (en) | 2007-07-09 | 2015-09-29 | Idera Pharmaceuticals, Inc. | Stabilized immune modulatory rna (simra) compounds |
| WO2009126933A2 (en) | 2008-04-11 | 2009-10-15 | Alnylam Pharmaceuticals, Inc. | Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components |
| US9433684B2 (en) | 2008-08-19 | 2016-09-06 | Nektar Therapeutics | Conjugates of small-interfering nucleic acids |
| US8637194B2 (en) * | 2008-09-02 | 2014-01-28 | Bio-Nano Power, Llc | Bio-nano power cells and their uses |
| RU2572826C2 (ru) * | 2008-12-02 | 2016-01-20 | Чиралджен, Лтд. | Способ синтеза модифицированных по атому фосфора нуклеиновых кислот |
| EP2395085B1 (en) * | 2009-02-04 | 2015-06-10 | Sungkyunkwan University Foundation for Corporate Collaboration | Small interference rna complex with increased intracellular transmission capacity |
| US9745574B2 (en) * | 2009-02-04 | 2017-08-29 | Rxi Pharmaceuticals Corporation | RNA duplexes with single stranded phosphorothioate nucleotide regions for additional functionality |
| KR101141544B1 (ko) | 2009-03-13 | 2012-05-03 | 한국과학기술원 | 에스아이알엔에이 다중 접합체 및 이의 제조방법 |
| DK2470656T3 (da) | 2009-08-27 | 2015-06-22 | Idera Pharmaceuticals Inc | Sammensætning til hæmning af genekspression og anvendelser heraf |
| KR101678876B1 (ko) * | 2010-01-15 | 2016-11-23 | 한국과학기술원 | 복합 유전자를 표적하는 ｓｉＲＮＡ 다중 접합체 및 이의 제조방법 |
| DK2539451T3 (da) | 2010-02-24 | 2016-04-04 | Arrowhead Res Corp | Sammensætninger til målrettet tilførsel af siRNA |
| EP2542247A4 (en) | 2010-03-01 | 2014-05-07 | Philadelphia Children Hospital | NUCLEIC ACID FOR ADDRESSING MULTIPLE REGIONS OF THE HCV GENOM |
| EP2652134B1 (en) | 2010-12-17 | 2017-03-01 | Arrowhead Pharmaceuticals, Inc. | Galactose cluster-pharmacokinetic modulator targeting moiety for sirna |
| US8691750B2 (en) | 2011-05-17 | 2014-04-08 | Axolabs Gmbh | Lipids and compositions for intracellular delivery of biologically active compounds |
| AU2012284265B2 (en) | 2011-07-19 | 2017-08-17 | Wave Life Sciences Ltd. | Methods for the synthesis of functionalized nucleic acids |
| HK1200484A1 (zh) | 2011-09-14 | 2015-08-07 | Translate Bio Ma, Inc. | 多聚寡核苷酸化合物 |
| KR101340290B1 (ko) | 2011-09-14 | 2013-12-11 | 한국과학기술원 | 유전자 표적용 ｓｉＲＮＡ 하이드로젤 및 그 제조방법 |
| AU2013243948A1 (en) | 2012-04-02 | 2014-10-30 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins associated with human disease |
| EP3241902B1 (en) | 2012-05-25 | 2018-02-28 | The Regents of The University of California | Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription |
| EP2895200B1 (en) | 2012-09-14 | 2019-11-06 | Translate Bio MA, Inc. | Multimeric oligonucleotide compounds |
| US8697359B1 (en) | 2012-12-12 | 2014-04-15 | The Broad Institute, Inc. | CRISPR-Cas systems and methods for altering expression of gene products |
| KR101629681B1 (ko) * | 2013-06-24 | 2016-06-14 | 건국대학교 산학협력단 | 다중 리간드가 도입된 에스아이알엔에이 접합체 |
| EP2845607A1 (en) | 2013-09-09 | 2015-03-11 | University of Vienna | Antisense oligonucleotides with improved pharmacokinetic properties |
| SG10201804960RA (en) | 2013-12-12 | 2018-07-30 | Alnylam Pharmaceuticals Inc | Complement component irna compositions and methods of use thereof |
| WO2015113922A1 (en) | 2014-01-30 | 2015-08-06 | Roche Innovation Center Copenhagen A/S | Poly oligomer compound with biocleavable conjugates |
| IL316159A (en) | 2015-06-15 | 2024-12-01 | Mpeg La Llc | Defined Oligonucleotide Multimers and Methods for Manufacture Thereof |
| EP3368671A1 (en) | 2015-10-26 | 2018-09-05 | Translate Bio Ma, Inc. | Methods and compositions for increasing smn expression |
| US10736960B2 (en) | 2016-01-05 | 2020-08-11 | Omeros Corporation | Methods for inhibiting fibrosis in a subject in need thereof |
| EP3576752A4 (en) * | 2017-02-06 | 2020-12-16 | Mpeg La, LLC | MULTIMERIC OLIGONUCLEOTIDES WITH REDUCED RENAL CLEARANCE |
| EP3733683A4 (en) | 2017-11-30 | 2022-04-06 | GeneMind Biosciences Company Limited | NUCLEOSIDE ANALOGUES, METHOD OF MANUFACTURE AND USE |
| AU2020319911A1 (en) | 2019-07-30 | 2022-02-24 | Mpeg La, L.L.C. | Subcutaneous delivery of multimeric oligonucleotides with enhanced bioactivity |
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