CN112080502A - 用于调节c9orf72表达的组合物 - Google Patents
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- CN112080502A CN112080502A CN202010989035.8A CN202010989035A CN112080502A CN 112080502 A CN112080502 A CN 112080502A CN 202010989035 A CN202010989035 A CN 202010989035A CN 112080502 A CN112080502 A CN 112080502A
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Families Citing this family (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9394333B2 (en) | 2008-12-02 | 2016-07-19 | Wave Life Sciences Japan | Method for the synthesis of phosphorus atom modified nucleic acids |
| MX342945B (es) | 2009-07-06 | 2016-10-18 | Ontorii Inc * | Profármacos de ácido nucleico novedosos y métodos de uso de los mismos. |
| DK2620428T3 (da) | 2010-09-24 | 2019-07-01 | Wave Life Sciences Ltd | Asymmetrisk hjælpegruppe |
| US9605019B2 (en) | 2011-07-19 | 2017-03-28 | Wave Life Sciences Ltd. | Methods for the synthesis of functionalized nucleic acids |
| SG11201500239VA (en) | 2012-07-13 | 2015-03-30 | Wave Life Sciences Japan | Asymmetric auxiliary group |
| US10443052B2 (en) | 2012-10-15 | 2019-10-15 | Ionis Pharmaceuticals, Inc. | Compositions for modulating C9ORF72 expression |
| ES2762326T5 (es) | 2012-10-15 | 2023-04-27 | Ionis Pharmaceuticals Inc | Métodos para modular la expresión de C9ORF72 |
| WO2014062736A1 (en) | 2012-10-15 | 2014-04-24 | Isis Pharmaceuticals, Inc. | Methods for monitoring c9orf72 expression |
| MX2016004651A (es) * | 2013-10-11 | 2016-08-05 | Ionis Pharmaceuticals Inc | Composiciones para modular la expresion de c9orf72. |
| ES2917473T3 (es) | 2014-01-16 | 2022-07-08 | Wave Life Sciences Ltd | Diseño quiral |
| AU2015231294B2 (en) | 2014-03-18 | 2020-10-29 | University Of Massachusetts | rAAV-based compositions and methods for treating amyotrophic lateral sclerosis |
| EP3722424A1 (en) * | 2015-04-16 | 2020-10-14 | Ionis Pharmaceuticals, Inc. | Compositions for modulating c9orf72 expression |
| MY192997A (en) | 2015-07-10 | 2022-09-20 | Ionis Pharmaceuticals Inc | Modulators of diacyglycerol acyltransferase 2 (dgat2) |
| WO2017079291A1 (en) | 2015-11-02 | 2017-05-11 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating c90rf72 |
| CN105663129B (zh) * | 2015-12-29 | 2020-05-15 | 山东大学 | 用于治疗肌萎缩侧索硬化和额颞叶痴呆的化合物与应用 |
| US20190142856A1 (en) * | 2016-04-13 | 2019-05-16 | Ionis Pharmaceuticals, Inc. | Methods for reducing c9orf72 expression |
| WO2018102397A1 (en) | 2016-11-29 | 2018-06-07 | PureTech Health LLC | Exosomes for delivery of therapeutic agents |
| EP3622073A4 (en) | 2017-05-09 | 2021-01-06 | University of Massachusetts | METHOD FOR TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS (ALS) |
| CA3072076A1 (en) | 2017-08-08 | 2019-02-14 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods thereof |
| JP7397488B2 (ja) | 2017-09-22 | 2023-12-13 | ユニバーシティ オブ マサチューセッツ | Sod1二重発現ベクターおよびその使用 |
| EP3701030A4 (en) * | 2017-10-23 | 2022-04-20 | Prevail Therapeutics, Inc. | GENE THERAPIES FOR NEURODEGENERATIVE DISEASES |
| WO2019094694A1 (en) | 2017-11-10 | 2019-05-16 | University Of Massachusetts | Compositions and methods for the treatment of expanded repeat-associated disorders |
| EA202091693A1 (ru) | 2018-01-12 | 2021-04-14 | Бристол-Маерс Сквибб Компани | Антисмысловые олигонуклеотиды, целенаправленно воздействующие на альфа-синуклеин, и их применения |
| MX2020007433A (es) | 2018-01-12 | 2020-09-14 | Bristol Myers Squibb Co | Oligonucleotidos antisentido que actuan sobre alfa-sinucleina, y usos de estos. |
| US20220280545A1 (en) * | 2018-09-10 | 2022-09-08 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating cln3 expression |
| US20210347866A1 (en) * | 2018-10-01 | 2021-11-11 | United Neuroscience | Peptide immunogen constructs directed against dipeptide repeat proteins from c9orf72 |
| MA54383A (fr) | 2018-12-06 | 2021-10-13 | Biogen Ma Inc | Protéine neurofilamenteuse pour guider une intervention thérapeutique dans la sclérose laterale amyotrophique |
| UY38562A (es) * | 2019-01-29 | 2020-08-31 | Ionis Pharmaceuticals Inc | Compuestos y métodos para reducir la expresión de app |
| EP3946374A4 (en) * | 2019-03-29 | 2023-07-19 | University of Massachusetts | OLIGONUCLEOTIDE-BASED MODULATION OF C9ORF72 |
| EP3966328A4 (en) * | 2019-05-06 | 2023-10-18 | University Of Massachusetts | Anti-c9orf72 oligonucleotides and related methods |
| PH12022551394A1 (en) * | 2019-12-13 | 2023-09-11 | Alnylam Pharmaceuticals Inc | Human chromosome 9 open reading frame 72 (c9orf72) irna agent compositions and methods of use thereof |
| WO2021159008A2 (en) | 2020-02-07 | 2021-08-12 | Maze Therapeutics, Inc. | Compositions and methods for treating neurodegenerative diseases |
| EP4110924A4 (en) * | 2020-02-28 | 2024-03-13 | Ionis Pharmaceuticals, Inc. | COMPOUNDS AND METHODS FOR MODULATING PRE-MRNA SPLICEING |
| EP4125930A4 (en) * | 2020-03-27 | 2025-06-04 | University Of Massachusetts | Dual-acting siRNA-based modulation of C9ORF72 |
| CA3171436A1 (en) * | 2020-04-09 | 2021-10-14 | Association Institut De Myologie | Antisense sequences for treating amyotrophic lateral sclerosis |
| US12384814B2 (en) | 2020-07-28 | 2025-08-12 | Ionis Pharmaceuticals, Inc. | Compounds and methods for reducing app expression |
| EP4320236A1 (en) | 2021-04-06 | 2024-02-14 | Maze Therapeutics, Inc. | Compositions and methods for treating tdp-43 proteinopathy |
| KR20250099775A (ko) | 2022-10-05 | 2025-07-02 | 트래이스 뉴로사이언스, 인크. | Unc13a 안티센스 올리고뉴클레오티드 및 그의 용도 |
| WO2025107038A1 (en) * | 2023-11-23 | 2025-05-30 | Murdoch University | Method of treating motor neurone disease |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013030588A1 (en) * | 2011-08-31 | 2013-03-07 | The University Of Manchester | Method for diagnosing a neurodegenerative disease |
| WO2013082548A1 (en) * | 2011-11-30 | 2013-06-06 | Sarepta Therapeutics, Inc. | Oligonucleotides for treating expanded repeat diseases |
| WO2013086207A1 (en) * | 2011-12-06 | 2013-06-13 | The Ohio State University | Non-ionic, low osmolar contrast agents for delivery of antisense oligonucleotides and treatment of disease |
| CN104968783A (zh) * | 2012-10-15 | 2015-10-07 | Isis制药公司 | 用于调节c9orf72表达的组合物 |
Family Cites Families (75)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6582908B2 (en) | 1990-12-06 | 2003-06-24 | Affymetrix, Inc. | Oligonucleotides |
| EP1044987B1 (en) | 1991-12-24 | 2006-02-15 | Isis Pharmaceuticals, Inc. | Gapped 2'-modified oligonucleotides |
| EP0673559A1 (en) | 1992-12-14 | 1995-09-27 | Honeywell Inc. | Motor system with individually controlled redundant windings |
| US5801154A (en) | 1993-10-18 | 1998-09-01 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of multidrug resistance-associated protein |
| US5681940A (en) | 1994-11-02 | 1997-10-28 | Icn Pharmaceuticals | Sugar modified nucleosides and oligonucleotides |
| 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 |
| US6770748B2 (en) | 1997-03-07 | 2004-08-03 | Takeshi Imanishi | Bicyclonucleoside and oligonucleotide analogue |
| US6794499B2 (en) | 1997-09-12 | 2004-09-21 | Exiqon A/S | Oligonucleotide analogues |
| DE69829760T3 (de) | 1997-09-12 | 2016-04-14 | Exiqon A/S | Bi- und tri-zyklische - nukleosid, nukleotid und oligonukleotid-analoga |
| 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 |
| US5998148A (en) | 1999-04-08 | 1999-12-07 | Isis Pharmaceuticals Inc. | Antisense modulation of microtubule-associated protein 4 expression |
| AU776362B2 (en) | 1999-05-04 | 2004-09-09 | Roche Innovation Center Copenhagen A/S | L-ribo-LNA analogues |
| US6525191B1 (en) | 1999-05-11 | 2003-02-25 | Kanda S. Ramasamy | Conformationally constrained L-nucleosides |
| DE19935303A1 (de) * | 1999-07-28 | 2001-02-08 | Aventis Pharma Gmbh | Oligonukleotide zur Inhibierung der Expression von humanem eg5 |
| USH2191H1 (en) | 2000-10-24 | 2007-06-05 | Snp Consortium | Identification and mapping of single nucleotide polymorphisms in the human genome |
| US20050019915A1 (en) | 2001-06-21 | 2005-01-27 | Bennett C. Frank | Antisense modulation of superoxide dismutase 1, soluble expression |
| CA2452458A1 (en) | 2001-07-03 | 2003-01-16 | Isis Pharmaceuticals, Inc. | Nuclease resistant chimeric oligonucleotides |
| EP1562971B1 (en) | 2002-11-05 | 2014-02-12 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
| AU2003295387A1 (en) | 2002-11-05 | 2004-06-03 | Isis Parmaceuticals, Inc. | Modified oligonucleotides for use in rna interference |
| US7250496B2 (en) | 2002-11-14 | 2007-07-31 | Rosetta Genomics Ltd. | Bioinformatically detectable group of novel regulatory genes and uses thereof |
| US8090542B2 (en) | 2002-11-14 | 2012-01-03 | Dharmacon Inc. | Functional and hyperfunctional siRNA |
| US7217807B2 (en) | 2002-11-26 | 2007-05-15 | Rosetta Genomics Ltd | Bioinformatically detectable group of novel HIV regulatory genes and uses thereof |
| WO2004106356A1 (en) | 2003-05-27 | 2004-12-09 | Syddansk Universitet | Functionalized nucleotide derivatives |
| DK1661905T3 (da) | 2003-08-28 | 2012-07-23 | Takeshi Imanishi | Hidtil ukendte syntetiske nukleinsyrer af N-O-krydsbindingstype |
| AU2004274021B2 (en) | 2003-09-18 | 2009-08-13 | Isis Pharmaceuticals, Inc. | 4'-thionucleosides and oligomeric compounds |
| US20050261233A1 (en) | 2004-04-21 | 2005-11-24 | Sanjay Bhanot | Modulation of glucose-6-phosphatase translocase expression |
| 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 |
| EP1766052A4 (en) | 2004-06-03 | 2009-12-16 | Isis Pharmaceuticals Inc | OLIGOMERIC CHIMERIC COMPOSITIONS WITH BRECH |
| WO2007056113A2 (en) | 2005-11-02 | 2007-05-18 | Cylene Pharmaceuticals, Inc. | Methods for targeting quadruplex sequences |
| JP5425474B2 (ja) | 2006-01-26 | 2014-02-26 | アイシス ファーマシューティカルズ, インコーポレーテッド | ハンチンチン対する、組成物及びその使用 |
| CA2640171C (en) | 2006-01-27 | 2014-10-28 | Isis Pharmaceuticals, Inc. | 6-modified bicyclic nucleic acid analogs |
| CA3044969A1 (en) | 2006-05-05 | 2007-12-21 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating gene expression |
| JP5441688B2 (ja) | 2006-05-11 | 2014-03-12 | アイシス ファーマシューティカルズ, インコーポレーテッド | 5’修飾二環式核酸類似体 |
| CA2666191C (en) * | 2006-10-09 | 2017-07-11 | Santaris Pharma A/S | Rna antagonist compounds for the modulation of pcsk9 |
| EP2104733A2 (en) | 2006-12-14 | 2009-09-30 | Novartis AG | Compositions and methods to treat muscular and cardiovascular disorders |
| WO2008101157A1 (en) | 2007-02-15 | 2008-08-21 | Isis Pharmaceuticals, Inc. | 5'-substituted-2'-f modified nucleosides and oligomeric compounds prepared therefrom |
| EP2170917B1 (en) | 2007-05-30 | 2012-06-27 | Isis Pharmaceuticals, Inc. | N-substituted-aminomethylene bridged bicyclic nucleic acid analogs |
| ES2386492T3 (es) | 2007-06-08 | 2012-08-21 | Isis Pharmaceuticals, Inc. | Análogos de ácidos nucleicos bicíclicos carbocíclicos |
| DE602007005629D1 (de) | 2007-06-18 | 2010-05-12 | Commissariat Energie Atomique | Reversibles siRNA-Silencing eines mutierten und endogenen Huntington-Wildtypgens und dessen Anwendung zur Behandlung von Morbus Huntington |
| CN101796062B (zh) | 2007-07-05 | 2014-07-30 | Isis制药公司 | 6-双取代双环核酸类似物 |
| US20090123928A1 (en) | 2007-10-11 | 2009-05-14 | The Johns Hopkins University | Genomic Landscapes of Human Breast and Colorectal Cancers |
| CA2704560A1 (en) * | 2007-11-05 | 2009-05-14 | Baltic Technology Development, Ltd. | Use of oligonucleotides with modified bases in hybridization of nucleic acids |
| WO2009067647A1 (en) | 2007-11-21 | 2009-05-28 | Isis Pharmaceuticals, Inc. | Carbocyclic alpha-l-bicyclic nucleic acid analogs |
| EP2265627A2 (en) | 2008-02-07 | 2010-12-29 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexitol nucleic acid analogs |
| WO2010019270A1 (en) | 2008-08-14 | 2010-02-18 | Isis Pharmaceuticals, Inc. | Modulation of prion expression |
| DK2356129T3 (da) | 2008-09-24 | 2013-05-13 | Isis Pharmaceuticals Inc | Substituerede alpha-L-bicykliske nukleosider |
| WO2010120820A1 (en) | 2009-04-13 | 2010-10-21 | Isis Pharmaceuticals, Inc. | Compositions and methods for modulation of smn2 splicing |
| KR20120050429A (ko) | 2009-06-15 | 2012-05-18 | 알닐람 파마슈티칼스 인코포레이티드 | Pcsk9 유전자를 표적으로 하는 지질 제형된 dsrna |
| US20140004565A1 (en) | 2009-07-06 | 2014-01-02 | Alnylam Pharmaceuticals, Inc. | Cell-based bioprocessing |
| WO2011005860A2 (en) | 2009-07-07 | 2011-01-13 | Alnylam Pharmaceuticals, Inc. | 5' phosphate mimics |
| WO2011017521A2 (en) | 2009-08-06 | 2011-02-10 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexose nucleic acid analogs |
| WO2011135396A1 (en) | 2010-04-30 | 2011-11-03 | Cellectis | Method for modulating double-strand break-induced homologous recombination |
| US20130217749A1 (en) * | 2010-06-10 | 2013-08-22 | Yale University | Modulation of phosphoenolpyruvate carboxykinase-mitchondrial (pepck-m) expression |
| WO2012005898A2 (en) | 2010-06-15 | 2012-01-12 | Alnylam Pharmaceuticals, Inc. | Chinese hamster ovary (cho) cell transcriptome, corresponding sirnas and uses thereof |
| US20130225659A1 (en) | 2010-07-19 | 2013-08-29 | Isis Pharmaceuticals, Inc. | Modulation of nuclear-retained rna |
| CA2822462A1 (en) | 2010-12-20 | 2012-06-28 | The General Hospital Corporation | Polycomb-associated non-coding rnas |
| WO2012092367A1 (en) | 2010-12-28 | 2012-07-05 | University Of Rochester | Nucleic acid binding compounds, methods of making, and use thereof |
| WO2012135736A2 (en) | 2011-04-01 | 2012-10-04 | Isis Pharmaceuticals, Inc. | Modulation of signal transducer and activator of transcription 3 (stat3) expression |
| MX347253B (es) | 2011-04-21 | 2017-04-20 | Ionis Pharmaceuticals Inc | Modulación de la expresión del virus de hepatitis b (vhb). |
| US20140255936A1 (en) | 2011-09-09 | 2014-09-11 | Mayo Foundation For Medical Education And Research | Detecting frontotemporal dementia and amyotrophic lateral sclerosis |
| AU2012340118A1 (en) * | 2011-11-17 | 2014-04-24 | Rheonix, Inc. | System and methods for selective molecular analysis |
| CA2870697C (en) | 2012-04-23 | 2021-11-23 | Prosensa Technologies B.V. | Rna modulating oligonucleotides with improved characteristics for the treatment of neuromuscular disorders |
| AU2013262709A1 (en) | 2012-05-16 | 2015-01-22 | Rana Therapeutics, Inc. | Compositions and methods for modulating MECP2 expression |
| WO2014062736A1 (en) | 2012-10-15 | 2014-04-24 | Isis Pharmaceuticals, Inc. | Methods for monitoring c9orf72 expression |
| ES2762326T5 (es) * | 2012-10-15 | 2023-04-27 | Ionis Pharmaceuticals Inc | Métodos para modular la expresión de C9ORF72 |
| LT2948777T (lt) | 2013-01-22 | 2019-09-25 | Deutsches Zentrum Für Neurodegenerative Erkrankungen E.V. | Baltymai su pasikartojančiais dipeptidais, kaip terapinis taikinys neurodegeneracinių ligų su padidėjusiu heksanukleotidų pasikartojimu atveju |
| MX2016004651A (es) * | 2013-10-11 | 2016-08-05 | Ionis Pharmaceuticals Inc | Composiciones para modular la expresion de c9orf72. |
| WO2016024205A1 (en) | 2014-08-15 | 2016-02-18 | Pfizer Inc. | Oligomers targeting hexanucleotide repeat expansion in human c9orf72 gene |
| AU2015326911C1 (en) | 2014-09-30 | 2025-12-18 | Neurimmune Holding Ag | Human-derived anti-dipeptide repeats (DPRs) antibody |
| WO2016060919A1 (en) | 2014-10-14 | 2016-04-21 | The Board Of Regents Of The University Of Texas System | Allele selective inhibition of mutant c9orf72 foci expression by duplex rnas targeting the expanded hexanucleotide repeat |
| EP3722424A1 (en) | 2015-04-16 | 2020-10-14 | Ionis Pharmaceuticals, Inc. | Compositions for modulating c9orf72 expression |
| WO2017079291A1 (en) | 2015-11-02 | 2017-05-11 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating c90rf72 |
| SG10201510101XA (en) | 2015-12-09 | 2017-07-28 | Au Optronics Corp | Evaporation apparatus and evaporation method |
| US20190142856A1 (en) | 2016-04-13 | 2019-05-16 | Ionis Pharmaceuticals, Inc. | Methods for reducing c9orf72 expression |
| CA3038548A1 (en) | 2016-09-30 | 2018-04-05 | Regeneron Pharmaceuticals, Inc. | Non-human animals having a hexanucleotide repeat expansion in a c9orf72 locus |
-
2014
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013030588A1 (en) * | 2011-08-31 | 2013-03-07 | The University Of Manchester | Method for diagnosing a neurodegenerative disease |
| WO2013082548A1 (en) * | 2011-11-30 | 2013-06-06 | Sarepta Therapeutics, Inc. | Oligonucleotides for treating expanded repeat diseases |
| WO2013086207A1 (en) * | 2011-12-06 | 2013-06-13 | The Ohio State University | Non-ionic, low osmolar contrast agents for delivery of antisense oligonucleotides and treatment of disease |
| CN104968783A (zh) * | 2012-10-15 | 2015-10-07 | Isis制药公司 | 用于调节c9orf72表达的组合物 |
Non-Patent Citations (2)
| Title |
|---|
| JOSHUA J. A. LEE ET AL.: "Antisense Therapy in Neurology", JOURNAL OF PERSONALIZED MEDICINE, vol. 3, no. 3, 2 August 2013 (2013-08-02), pages 144 - 176, XP055163807, DOI: 10.3390/jpm3030144 * |
| SORANA CIURA ET AL.: "Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis", ANN NEUROL ., vol. 74, no. 2, 30 May 2013 (2013-05-30), pages 180 - 187, XP071640915, DOI: 10.1002/ana.23946 * |
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