CA2732343C - Selective inhibition of polyglutamine protein expression - Google Patents
Selective inhibition of polyglutamine protein expression Download PDFInfo
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- CA2732343C CA2732343C CA2732343A CA2732343A CA2732343C CA 2732343 C CA2732343 C CA 2732343C CA 2732343 A CA2732343 A CA 2732343A CA 2732343 A CA2732343 A CA 2732343A CA 2732343 C CA2732343 C CA 2732343C
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| PCT/US2009/051938 WO2010014592A1 (en) | 2008-07-29 | 2009-07-28 | Selective inhibition of polyglutamine protein expression |
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| WO2008018795A1 (en) | 2006-08-11 | 2008-02-14 | Prosensa Technologies B.V. | Methods and means for treating dna repeat instability associated genetic disorders |
| PT2203173E (pt) | 2007-10-26 | 2016-03-15 | Academisch Ziekenhuis Leiden | Resumo |
| WO2011097388A1 (en) * | 2010-02-03 | 2011-08-11 | Alnylam Pharmaceuticals, Inc. | Selective inhibition of polyglutamine protein expression |
| WO2011097641A1 (en) * | 2010-02-08 | 2011-08-11 | Isis Pharmaceuticals, Inc. | Methods and compositions useful in treatment of diseases or conditions related to repeat expansion |
| KR20180105730A (ko) * | 2010-07-19 | 2018-09-28 | 아이오니스 파마수티컬즈, 인코포레이티드 | 근육긴장성 이영양증-단백질 키나제(dmpk) 발현의 조절 방법 |
| DK2638163T3 (en) | 2010-11-12 | 2017-07-24 | Massachusetts Gen Hospital | POLYCOMB-ASSOCIATED NON-CODING RNAs |
| US9920317B2 (en) | 2010-11-12 | 2018-03-20 | The General Hospital Corporation | Polycomb-associated non-coding RNAs |
| US9976138B2 (en) | 2011-08-29 | 2018-05-22 | Ionis Pharmaceuticals, Inc. | Methods and compounds useful in conditions related to repeat expansion |
| NZ627896A (en) | 2012-01-27 | 2016-11-25 | Biomarin Technologies B V | Rna modulating oligonucleotides with improved characteristics for the treatment of duchenne and becker muscular dystrophy |
| EP2839008A4 (en) * | 2012-03-12 | 2015-12-02 | Roche Innovation Ct Copenhagen As | COMPOSITIONS AND METHODS FOR MODULATING ATXN3 EXPRESSION |
| BR112014026285B1 (pt) | 2012-04-23 | 2021-08-31 | Biomarin Technologies B.V | Oligonucleotídeos moduladores de rna com características melhoradas para o tratamento de distúrbios neuromusculares |
| US10837014B2 (en) | 2012-05-16 | 2020-11-17 | Translate Bio Ma, Inc. | Compositions and methods for modulating SMN gene family expression |
| WO2013173638A1 (en) | 2012-05-16 | 2013-11-21 | Rana Therapeutics, Inc. | Compositions and methods for modulating smn gene family expression |
| EP2850188A4 (en) | 2012-05-16 | 2016-01-20 | Rana Therapeutics Inc | COMPOSITIONS AND METHOD FOR MODULATING THE EXPRESSION OF THE HEMOGLOBIN GENE FAMILIES |
| JP2015518712A (ja) | 2012-05-16 | 2015-07-06 | ラナ セラピューティクス インコーポレイテッド | Mecp2発現を調節するための組成物及び方法 |
| JP2015518713A (ja) | 2012-05-16 | 2015-07-06 | ラナ セラピューティクス インコーポレイテッド | Utrn発現を調節するための組成物及び方法 |
| CN104583401A (zh) | 2012-05-16 | 2015-04-29 | Rana医疗有限公司 | 用于调节atp2a2表达的组合物和方法 |
| WO2015017675A2 (en) | 2013-07-31 | 2015-02-05 | Isis Pharmaceuticals, Inc. | Methods and compounds useful in conditions related to repeat expansion |
| TW201536329A (zh) | 2013-08-09 | 2015-10-01 | Isis Pharmaceuticals Inc | 用於調節失養性肌強直蛋白質激酶(dmpk)表現之化合物及方法 |
| US10006027B2 (en) | 2014-03-19 | 2018-06-26 | Ionis Pharmaceuticals, Inc. | Methods for modulating Ataxin 2 expression |
| WO2015143246A1 (en) | 2014-03-19 | 2015-09-24 | Isis Pharmaceuticals, Inc. | Compositions for modulating ataxin 2 expression |
| US10858650B2 (en) | 2014-10-30 | 2020-12-08 | The General Hospital Corporation | Methods for modulating ATRX-dependent gene repression |
| WO2016130943A1 (en) | 2015-02-13 | 2016-08-18 | Rana Therapeutics, Inc. | Hybrid oligonucleotides and uses thereof |
| WO2016149455A2 (en) | 2015-03-17 | 2016-09-22 | The General Hospital Corporation | The rna interactome of polycomb repressive complex 1 (prc1) |
| US10533175B2 (en) | 2015-09-25 | 2020-01-14 | Ionis Pharmaceuticals, Inc. | Compositions and methods for modulating Ataxin 3 expression |
| AU2016344384A1 (en) | 2015-10-26 | 2018-05-17 | Translate Bio Ma, Inc. | Nanoparticle formulations for delivery of nucleic acid complexes |
| EP3397288A4 (en) | 2015-12-31 | 2019-09-11 | Ionis Pharmaceuticals, Inc. | PROCESS FOR REDUCING ATAXIN-2 EXPRESSION |
| JP6430999B2 (ja) * | 2016-06-24 | 2018-11-28 | トヨタ自動車株式会社 | 自動車用エンジン冷却液組成物、自動車用エンジン濃縮冷却液組成物及び内燃機関の運転方法 |
| JOP20190104A1 (ar) | 2016-11-10 | 2019-05-07 | Ionis Pharmaceuticals Inc | مركبات وطرق لتقليل التعبير عن atxn3 |
| WO2019217708A1 (en) | 2018-05-09 | 2019-11-14 | Ionis Pharmaceuticals, Inc. | Compounds and methods for reducing atxn3 expression |
| WO2019233922A1 (en) | 2018-06-05 | 2019-12-12 | F. Hoffmann-La Roche Ag | Oligonucleotides for modulating atxn2 expression |
| MX2021000922A (es) | 2018-07-25 | 2021-03-31 | Ionis Pharmaceuticals Inc | Compuestos y metodos para reducir la expresion de la atxn2. |
| US11286485B2 (en) | 2019-04-04 | 2022-03-29 | Hoffmann-La Roche Inc. | Oligonucleotides for modulating ATXN2 expression |
| JP2023520405A (ja) * | 2020-03-30 | 2023-05-17 | ニューベース セラピューティクス, インコーポレイテッド | 改変ペプチド核酸組成物 |
| BR112023019981A2 (pt) | 2021-03-29 | 2023-12-12 | Alnylam Pharmaceuticals Inc | Composições do agente irna de huntingtina (htt) e métodos de uso das mesmas |
| US11833221B2 (en) | 2021-09-01 | 2023-12-05 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds for reducing DMPK expression |
Family Cites Families (83)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4529561A (en) | 1978-03-24 | 1985-07-16 | The Regents Of The University Of California | Method for producing liposomes in selected size range |
| US5118800A (en) | 1983-12-20 | 1992-06-02 | California Institute Of Technology | Oligonucleotides possessing a primary amino group in the terminal nucleotide |
| FR2567892B1 (fr) | 1984-07-19 | 1989-02-17 | Centre Nat Rech Scient | Nouveaux oligonucleotides, leur procede de preparation et leurs applications comme mediateurs dans le developpement des effets des interferons |
| US4737323A (en) | 1986-02-13 | 1988-04-12 | Liposome Technology, Inc. | Liposome extrusion method |
| US5591722A (en) | 1989-09-15 | 1997-01-07 | Southern Research Institute | 2'-deoxy-4'-thioribonucleosides and their antiviral activity |
| DE69033495T2 (de) | 1989-10-24 | 2000-07-20 | Isis Pharmaceuticals, Inc. | 2'-modifizierte nukleotide |
| US6005087A (en) | 1995-06-06 | 1999-12-21 | Isis Pharmaceuticals, Inc. | 2'-modified oligonucleotides |
| US5646265A (en) | 1990-01-11 | 1997-07-08 | Isis Pharmceuticals, Inc. | Process for the preparation of 2'-O-alkyl purine phosphoramidites |
| US6753423B1 (en) | 1990-01-11 | 2004-06-22 | Isis Pharmaceuticals, Inc. | Compositions and methods for enhanced biostability and altered biodistribution of oligonucleotides in mammals |
| US5670633A (en) | 1990-01-11 | 1997-09-23 | Isis Pharmaceuticals, Inc. | Sugar modified oligonucleotides that detect and modulate gene expression |
| GB9009980D0 (en) | 1990-05-03 | 1990-06-27 | Amersham Int Plc | Phosphoramidite derivatives,their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides |
| EP0455905B1 (en) | 1990-05-11 | 1998-06-17 | Microprobe Corporation | Dipsticks for nucleic acid hybridization assays and methods for covalently immobilizing oligonucleotides |
| US6582908B2 (en) | 1990-12-06 | 2003-06-24 | Affymetrix, Inc. | Oligonucleotides |
| DE59208572D1 (de) | 1991-10-17 | 1997-07-10 | Ciba Geigy Ag | Bicyclische Nukleoside, Oligonukleotide, Verfahren zu deren Herstellung und Zwischenprodukte |
| US5359044A (en) | 1991-12-13 | 1994-10-25 | Isis Pharmaceuticals | Cyclobutyl oligonucleotide surrogates |
| US5700922A (en) | 1991-12-24 | 1997-12-23 | Isis Pharmaceuticals, Inc. | PNA-DNA-PNA chimeric macromolecules |
| FR2687679B1 (fr) | 1992-02-05 | 1994-10-28 | Centre Nat Rech Scient | Oligothionucleotides. |
| EP0577558A2 (de) | 1992-07-01 | 1994-01-05 | Ciba-Geigy Ag | Carbocyclische Nukleoside mit bicyclischen Ringen, Oligonukleotide daraus, Verfahren zu deren Herstellung, deren Verwendung und Zwischenproduckte |
| JPH08504559A (ja) | 1992-12-14 | 1996-05-14 | ハネウエル・インコーポレーテッド | 個別に制御される冗長巻線を有するモータシステム |
| CA2159631A1 (en) | 1993-03-30 | 1994-10-13 | Sanofi | Acyclic nucleoside analogs and oligonucleotide sequences containing them |
| DE4311944A1 (de) | 1993-04-10 | 1994-10-13 | Degussa | Umhüllte Natriumpercarbonatpartikel, Verfahren zu deren Herstellung und sie enthaltende Wasch-, Reinigungs- und Bleichmittelzusammensetzungen |
| FR2705099B1 (fr) | 1993-05-12 | 1995-08-04 | Centre Nat Rech Scient | Oligonucléotides phosphorothioates triesters et procédé de préparation. |
| US5801154A (en) | 1993-10-18 | 1998-09-01 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of multidrug resistance-associated protein |
| US5446137B1 (en) | 1993-12-09 | 1998-10-06 | Behringwerke Ag | Oligonucleotides containing 4'-substituted nucleotides |
| US5595756A (en) | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
| US5519134A (en) | 1994-01-11 | 1996-05-21 | Isis Pharmaceuticals, Inc. | Pyrrolidine-containing monomers and oligomers |
| US5627053A (en) | 1994-03-29 | 1997-05-06 | Ribozyme Pharmaceuticals, Inc. | 2'deoxy-2'-alkylnucleotide containing nucleic acid |
| US5597909A (en) | 1994-08-25 | 1997-01-28 | Chiron Corporation | Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use |
| US5792747A (en) | 1995-01-24 | 1998-08-11 | The Administrators Of The Tulane Educational Fund | Highly potent agonists of growth hormone releasing hormone |
| US6043060A (en) | 1996-11-18 | 2000-03-28 | Imanishi; Takeshi | Nucleotide analogues |
| US6770748B2 (en) | 1997-03-07 | 2004-08-03 | Takeshi Imanishi | Bicyclonucleoside and oligonucleotide analogue |
| JP3756313B2 (ja) | 1997-03-07 | 2006-03-15 | 武 今西 | 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体 |
| ATE321882T1 (de) | 1997-07-01 | 2006-04-15 | Isis Pharmaceuticals Inc | Zusammensetzungen und verfahren zur verabreichung von oligonukleotiden über die speiseröhre |
| US6794499B2 (en) | 1997-09-12 | 2004-09-21 | Exiqon A/S | Oligonucleotide analogues |
| KR100414936B1 (ko) | 1997-09-12 | 2004-01-13 | 엑시콘 에이/에스 | 이환 및 삼환 뉴클레오시드, 뉴클레오타이드 및올리고뉴클레오타이드 동족체 |
| US20030228597A1 (en) | 1998-04-13 | 2003-12-11 | Cowsert Lex M. | Identification of genetic targets for modulation by oligonucleotides and generation of oligonucleotides for gene modulation |
| US6043352A (en) | 1998-08-07 | 2000-03-28 | Isis Pharmaceuticals, Inc. | 2'-O-Dimethylaminoethyloxyethyl-modified oligonucleotides |
| NZ513402A (en) | 1999-02-12 | 2003-06-30 | Sankyo Co | Novel nucleosides and oligonucleotide analogues |
| US7084125B2 (en) | 1999-03-18 | 2006-08-01 | Exiqon A/S | Xylo-LNA analogues |
| US5998148A (en) | 1999-04-08 | 1999-12-07 | Isis Pharmaceuticals Inc. | Antisense modulation of microtubule-associated protein 4 expression |
| PT1178999E (pt) | 1999-05-04 | 2007-06-26 | Santaris Pharma As | Análogos de l-ribo-lna |
| US6525191B1 (en) | 1999-05-11 | 2003-02-25 | Kanda S. Ramasamy | Conformationally constrained L-nucleosides |
| JP4151751B2 (ja) | 1999-07-22 | 2008-09-17 | 第一三共株式会社 | 新規ビシクロヌクレオシド類縁体 |
| US6147200A (en) | 1999-08-19 | 2000-11-14 | Isis Pharmaceuticals, Inc. | 2'-O-acetamido modified monomers and oligomers |
| US6632616B2 (en) | 2000-03-16 | 2003-10-14 | Duke University | Compounds that selectively bind to expanded polyglutamine repeat domains and methods of use thereof |
| AU4819101A (en) | 2000-04-13 | 2001-10-30 | University Of British Columbia, The | Modulating cell survival by modulating huntingtin function |
| AU2001296412A1 (en) | 2000-09-29 | 2002-04-08 | Isis Pharmaceuticals, Inc. | Antisense modulation of mekk4 expression |
| US20050191638A1 (en) | 2002-02-20 | 2005-09-01 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
| US20040096880A1 (en) | 2001-08-07 | 2004-05-20 | Kmiec Eric B. | Compositions and methods for the treatment of diseases exhibiting protein misassembly and aggregation |
| US20030109476A1 (en) | 2001-08-07 | 2003-06-12 | Kmiec Eric B. | Compositions and methods for the prevention and treatment of Huntington's disease |
| EP2221377B2 (en) | 2002-02-01 | 2017-05-17 | Life Technologies Corporation | Oligonucleotide compositions with enhanced efficiency |
| US20050096284A1 (en) | 2002-02-20 | 2005-05-05 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
| US7569575B2 (en) | 2002-05-08 | 2009-08-04 | Santaris Pharma A/S | Synthesis of locked nucleic acid derivatives |
| US20040092465A1 (en) | 2002-11-11 | 2004-05-13 | Isis Pharmaceuticals Inc. | Modulation of huntingtin interacting protein 1 expression |
| US20040102398A1 (en) | 2002-11-23 | 2004-05-27 | Isis Pharmaceuticals Inc. | Modulation of B7H expression |
| US20050042646A1 (en) | 2002-08-05 | 2005-02-24 | Davidson Beverly L. | RNA interference suppresion of neurodegenerative diseases and methods of use thereof |
| US20050106731A1 (en) | 2002-08-05 | 2005-05-19 | Davidson Beverly L. | siRNA-mediated gene silencing with viral vectors |
| US20080274989A1 (en) | 2002-08-05 | 2008-11-06 | University Of Iowa Research Foundation | Rna Interference Suppression of Neurodegenerative Diseases and Methods of Use Thereof |
| US20050255086A1 (en) | 2002-08-05 | 2005-11-17 | Davidson Beverly L | Nucleic acid silencing of Huntington's Disease gene |
| WO2004027030A2 (en) | 2002-09-18 | 2004-04-01 | Isis Pharmaceuticals, Inc. | Efficient reduction of target rna’s by single- and double-stranded oligomeric compounds |
| US20040219565A1 (en) | 2002-10-21 | 2004-11-04 | Sakari Kauppinen | Oligonucleotides useful for detecting and analyzing nucleic acids of interest |
| CA2504694C (en) | 2002-11-05 | 2013-10-01 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
| US7250496B2 (en) | 2002-11-14 | 2007-07-31 | Rosetta Genomics Ltd. | Bioinformatically detectable group of novel regulatory genes and uses thereof |
| DK2284266T3 (da) | 2002-11-14 | 2014-01-13 | Thermo Fisher Scient Biosciences Inc | sIRNA-MOLEKYLE MOD TP53 |
| US7250289B2 (en) | 2002-11-20 | 2007-07-31 | Affymetrix, Inc. | Methods of genetic analysis of mouse |
| AU2004239114B2 (en) * | 2003-05-14 | 2008-03-13 | Japan Science And Technology Agency | Inhibition of the expression of huntingtin gene |
| JP4731324B2 (ja) | 2003-08-28 | 2011-07-20 | 武 今西 | N−o結合性架橋構造型新規人工核酸 |
| EP2821085B1 (en) | 2003-09-12 | 2020-04-29 | University of Massachusetts | Rna interference for the treatment of gain-of-function disorders |
| WO2005045032A2 (en) | 2003-10-20 | 2005-05-19 | Sima Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF EARLY GROWTH RESPONSE GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| EP1735443A2 (en) | 2004-04-14 | 2006-12-27 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED TREATMENT OF POLYGLUTAMINE (POLYQ) REPEAT EXPANSION DISEASES USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| AU2005248147A1 (en) | 2004-05-11 | 2005-12-08 | Alphagen Co., Ltd. | Polynucleotides for causing RNA interference and method for inhibiting gene expression using the same |
| EP1765847A4 (en) | 2004-05-27 | 2010-10-20 | Alnylam Pharmaceuticals Inc | NUCLEASERESISTENT DOUBLE-STRANDED RIBONUCLEIC ACID |
| CA2568735A1 (en) | 2004-06-03 | 2005-12-22 | Isis Pharmaceuticals, Inc. | Double strand compositions comprising differentially modified strands for use in gene modulation |
| US7323308B2 (en) | 2004-09-03 | 2008-01-29 | Affymetrix, Inc. | Methods of genetic analysis of E. coli |
| EP1937066A4 (en) | 2005-08-18 | 2008-12-24 | Alnylam Pharmaceuticals Inc | METHOD AND COMPOSITIONS FOR THE TREATMENT OF NERVOUS DISEASES |
| US7320965B2 (en) | 2005-10-28 | 2008-01-22 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of Huntingtin gene |
| EP2431467A3 (en) * | 2005-11-17 | 2012-05-02 | Board Of Regents, The University Of Texas | Modulation of gene expression by oligomers targeted to chromosomal DNA |
| EP2161038B1 (en) | 2006-01-26 | 2013-12-25 | Isis Pharmaceuticals, Inc. | Compositions and their uses directed to Huntingtin |
| WO2007136989A2 (en) | 2006-05-05 | 2007-11-29 | Isis Pharmaceuticals, Inc. | Compounds and methods for modulating expression of dgat2 |
| WO2008018795A1 (en) * | 2006-08-11 | 2008-02-14 | Prosensa Technologies B.V. | Methods and means for treating dna repeat instability associated genetic disorders |
| EP2188298B1 (en) | 2007-08-15 | 2013-09-18 | Isis Pharmaceuticals, Inc. | Tetrahydropyran nucleic acid analogs |
| RU2562861C2 (ru) | 2009-09-11 | 2015-09-10 | Айсис Фармасьютикалс, Инк. | Модуляция экспрессии гентингтина |
| WO2011097388A1 (en) | 2010-02-03 | 2011-08-11 | Alnylam Pharmaceuticals, Inc. | Selective inhibition of polyglutamine protein expression |
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| EP2317847B1 (en) | 2019-04-17 |
| US8901095B2 (en) | 2014-12-02 |
| AU2009276763B2 (en) | 2015-07-16 |
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