CA2907694A1 - Oligonucleotide modulators of b-cell cll/lymphoma 11a (bcl11a) and uses thereof - Google Patents
Oligonucleotide modulators of b-cell cll/lymphoma 11a (bcl11a) and uses thereof Download PDFInfo
- Publication number
- CA2907694A1 CA2907694A1 CA2907694A CA2907694A CA2907694A1 CA 2907694 A1 CA2907694 A1 CA 2907694A1 CA 2907694 A CA2907694 A CA 2907694A CA 2907694 A CA2907694 A CA 2907694A CA 2907694 A1 CA2907694 A1 CA 2907694A1
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- Prior art keywords
- seq
- antisense oligonucleotide
- bcl11a
- mcs
- lna
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
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- C12N2310/315—Phosphorothioates
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- C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
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Applications Claiming Priority (3)
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| US201361827484P | 2013-05-24 | 2013-05-24 | |
| US61/827,484 | 2013-05-24 | ||
| PCT/EP2014/060813 WO2014188001A1 (en) | 2013-05-24 | 2014-05-26 | Oligonucleotide modulators of b-cell cll/lymphoma 11a (bcl11a) and uses thereof |
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| CA2907694A1 true CA2907694A1 (en) | 2014-11-27 |
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| CA2907694A Abandoned CA2907694A1 (en) | 2013-05-24 | 2014-05-26 | Oligonucleotide modulators of b-cell cll/lymphoma 11a (bcl11a) and uses thereof |
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| EP (1) | EP3004352B1 (enExample) |
| JP (1) | JP2016520310A (enExample) |
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| CN (1) | CN105247052A (enExample) |
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| MX (1) | MX363846B (enExample) |
| RU (1) | RU2015155332A (enExample) |
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| SG171914A1 (en) | 2008-12-02 | 2011-07-28 | Chiralgen Ltd | Method for the synthesis of phosphorus atom modified nucleic acids |
| IN2012DN00720A (enExample) | 2009-07-06 | 2015-06-19 | Ontorii Inc | |
| WO2012039448A1 (ja) | 2010-09-24 | 2012-03-29 | 株式会社キラルジェン | 不斉補助基 |
| MX347361B (es) | 2011-07-19 | 2017-04-12 | Wave Life Sciences Ltd | Metodos para la sintesis de acidos nucleicos funcionalizados. |
| EP2872147B1 (en) | 2012-07-13 | 2022-12-21 | Wave Life Sciences Ltd. | Method for making chiral oligonucleotides |
| EP2872485B1 (en) | 2012-07-13 | 2020-12-16 | Wave Life Sciences Ltd. | Asymmetric auxiliary group |
| US10144933B2 (en) | 2014-01-15 | 2018-12-04 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator |
| JPWO2015108048A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
| CN106068325B (zh) | 2014-01-16 | 2021-07-09 | 波涛生命科学有限公司 | 手性设计 |
| WO2017184082A1 (en) * | 2016-04-22 | 2017-10-26 | Nanyang Technological University | A lymphocyte permeating chimeric oligonucleotide, methods and uses thereof |
| US11957718B2 (en) | 2016-12-22 | 2024-04-16 | University Of Maryland, Baltimore | Methods for generating multipotent stem cells from tonsillar biopsies |
| TW201839136A (zh) | 2017-02-06 | 2018-11-01 | 瑞士商諾華公司 | 治療血色素異常症之組合物及方法 |
| MX2021005507A (es) * | 2018-11-13 | 2021-06-18 | Lipigon Pharmaceuticals Ab | Oligonucleotidos de angptl4 que influyen en la regulacion del metabolismo de los acidos grasos. |
| CN114903992B (zh) * | 2022-04-18 | 2024-01-16 | 南通大学 | 转录因子bcl11a在制备施万细胞调控药物中的应用 |
| WO2025024334A1 (en) | 2023-07-21 | 2025-01-30 | Marrow Therapeutics, Inc. | Hematopoietic cell targeting conjugates and related methods |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6617442B1 (en) | 1999-09-30 | 2003-09-09 | Isis Pharmaceuticals, Inc. | Human Rnase H1 and oligonucleotide compositions thereof |
| CA2506576C (en) | 2002-11-18 | 2018-03-06 | Santaris Pharma A/S | Antisense gapmer oligonucleotides |
| WO2007031091A2 (en) | 2005-09-15 | 2007-03-22 | Santaris Pharma A/S | Rna antagonist compounds for the modulation of p21 ras expression |
| JP5342881B2 (ja) | 2006-01-27 | 2013-11-13 | 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 | ６−修飾された二環式核酸類似体 |
| EP2505646A1 (en) | 2006-05-05 | 2012-10-03 | Isis Pharmaceuticals, Inc. | Compounds and methods for modulating expression of CRP |
| US7547684B2 (en) | 2006-05-11 | 2009-06-16 | Isis Pharmaceuticals, Inc. | 5′-modified bicyclic nucleic acid analogs |
| EP2090127A2 (en) | 2006-10-30 | 2009-08-19 | Nokia Corporation | Method, apparatus and system providing operator controlled mobility for user equipment |
| DK2149605T3 (da) * | 2007-03-22 | 2013-09-30 | Santaris Pharma As | Korte RNA antagonist forbindelser til modulering af det ønskede mRNA |
| EP2170917B1 (en) | 2007-05-30 | 2012-06-27 | Isis Pharmaceuticals, Inc. | N-substituted-aminomethylene bridged bicyclic nucleic acid analogs |
| EP2173760B2 (en) | 2007-06-08 | 2015-11-04 | Isis Pharmaceuticals, Inc. | Carbocyclic bicyclic nucleic acid analogs |
| CA2692579C (en) | 2007-07-05 | 2016-05-03 | Isis Pharmaceuticals, Inc. | 6-disubstituted bicyclic nucleic acid analogs |
| WO2009067647A1 (en) | 2007-11-21 | 2009-05-28 | Isis Pharmaceuticals, Inc. | Carbocyclic alpha-l-bicyclic nucleic acid analogs |
| WO2009071680A2 (en) * | 2007-12-07 | 2009-06-11 | Santaris Pharma A/S | Rna antagonist compounds for the modulation of mcl-1 |
| WO2009090182A1 (en) | 2008-01-14 | 2009-07-23 | Santaris Pharma A/S | C4'-substituted - dna nucleotide gapmer oligonucleotides |
| EP2265627A2 (en) | 2008-02-07 | 2010-12-29 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexitol nucleic acid analogs |
| US8846639B2 (en) | 2008-04-04 | 2014-09-30 | Isis Pharmaceutical, Inc. | Oligomeric compounds comprising bicyclic nucleosides and having reduced toxicity |
| DK2334794T3 (en) | 2008-09-15 | 2017-02-20 | Children's Medical Center Corp | MODULATION OF BCL11A FOR TREATMENT OF HEMOGLOBINOPATHIES |
| WO2010036698A1 (en) | 2008-09-24 | 2010-04-01 | Isis Pharmaceuticals, Inc. | Substituted alpha-l-bicyclic nucleosides |
| EP2462153B1 (en) | 2009-08-06 | 2015-07-29 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexose nucleic acid analogs |
| US8779118B2 (en) | 2010-01-11 | 2014-07-15 | Isis Pharmaceuticals, Inc. | Base modified bicyclic nucleosides and oligomeric compounds prepared therefrom |
| US9193752B2 (en) | 2010-03-17 | 2015-11-24 | Isis Pharmaceuticals, Inc. | 5′-substituted bicyclic nucleosides and oligomeric compounds prepared therefrom |
| WO2012073047A2 (en) * | 2010-12-03 | 2012-06-07 | Genome Research Limited | Compositions and methods |
| US9127275B2 (en) | 2010-12-10 | 2015-09-08 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of klf-1 and bcl11a genes |
| CN102329794B (zh) * | 2011-09-28 | 2012-11-14 | 暨南大学 | 抑制BCL11A表达和肿瘤性B细胞增殖的Bcl11a siRNA-585及其应用 |
| CN102352356B (zh) * | 2011-09-28 | 2012-12-05 | 暨南大学 | 抑制BCL11A表达和肿瘤性B细胞增殖的Bcl11a siRNA-2292及其应用 |
| WO2013055985A1 (en) * | 2011-10-12 | 2013-04-18 | Children's Medical Center Corporation | Combinatorial compositions and methods of treating hemoglobinopathies |
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- 2014-05-26 US US14/892,497 patent/US20160130582A1/en not_active Abandoned
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| EP3004352B1 (en) | 2017-09-27 |
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| KR20160013110A (ko) | 2016-02-03 |
| RU2015155332A (ru) | 2017-06-27 |
| MX363846B (es) | 2019-04-05 |
| CN105247052A (zh) | 2016-01-13 |
| BR112015029327A2 (pt) | 2017-09-19 |
| HK1213595A1 (zh) | 2016-07-08 |
| WO2014188001A1 (en) | 2014-11-27 |
| EP3004352A1 (en) | 2016-04-13 |
| US20160130582A1 (en) | 2016-05-12 |
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