TW202027797A - 用於治療α-1抗胰蛋白酶不足的組成物及方法 - Google Patents
用於治療α-1抗胰蛋白酶不足的組成物及方法 Download PDFInfo
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| JP7460643B2 (ja) | 2018-10-16 | 2024-04-02 | ブルーアレル, エルエルシー | 遺伝子へのdnaの標的化挿入のための方法 |
| JP7578590B2 (ja) | 2018-10-18 | 2024-11-06 | インテリア セラピューティクス,インコーポレーテッド | 第ix因子を発現するための組成物及び方法 |
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| US12521451B2 (en) | 2019-11-08 | 2026-01-13 | Regeneron Pharmaceuticals, Inc. | CRISPR and AAV strategies for x-linked juvenile retinoschisis therapy |
| KR102366490B1 (ko) * | 2020-10-20 | 2022-02-23 | 에스티팜 주식회사 | 5'-캡핑된 rna 합성용 올리고뉴클레오티드 |
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| SG191561A1 (en) | 2008-08-22 | 2013-07-31 | Sangamo Biosciences Inc | Methods and compositions for targeted single-stranded cleavage and targeted integration |
| EP2534163B1 (en) | 2010-02-09 | 2015-11-04 | Sangamo BioSciences, Inc. | Targeted genomic modification with partially single-stranded donor molecules |
| 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 |
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| WO2014093694A1 (en) | 2012-12-12 | 2014-06-19 | The Broad Institute, Inc. | Crispr-cas nickase systems, methods and compositions for sequence manipulation in eukaryotes |
| EP3608308B1 (en) | 2013-03-08 | 2021-07-21 | Novartis AG | Lipids and lipid compositions for the delivery of active agents |
| CN105683376A (zh) * | 2013-05-15 | 2016-06-15 | 桑格摩生物科学股份有限公司 | 用于治疗遗传病状的方法和组合物 |
| ES2895651T3 (es) | 2013-12-19 | 2022-02-22 | Novartis Ag | Lípidos y composiciones lipídicas para la administración de agentes activos |
| US20150376586A1 (en) | 2014-06-25 | 2015-12-31 | Caribou Biosciences, Inc. | RNA Modification to Engineer Cas9 Activity |
| EP3169309B1 (en) | 2014-07-16 | 2023-05-10 | Novartis AG | Method of encapsulating a nucleic acid in a lipid nanoparticle host |
| CA2969151A1 (en) | 2014-12-23 | 2016-06-30 | Syngenta Participations Ag | Methods and compositions for identifying and enriching for cells comprising site specific genomic modifications |
| EP3265559B1 (en) | 2015-03-03 | 2021-01-06 | The General Hospital Corporation | Engineered crispr-cas9 nucleases with altered pam specificity |
| US11279928B2 (en) | 2015-06-29 | 2022-03-22 | Massachusetts Institute Of Technology | Compositions comprising nucleic acids and methods of using the same |
| CA3006618A1 (en) * | 2015-12-01 | 2017-06-08 | Crispr Therapeutics Ag | Materials and methods for treatment of alpha-1 antitrypsin deficiency |
| US11845933B2 (en) | 2016-02-03 | 2023-12-19 | Massachusetts Institute Of Technology | Structure-guided chemical modification of guide RNA and its applications |
| WO2017165862A1 (en) * | 2016-03-25 | 2017-09-28 | Editas Medicine, Inc. | Systems and methods for treating alpha 1-antitrypsin (a1at) deficiency |
| TWI773666B (zh) | 2016-03-30 | 2022-08-11 | 美商英特利亞醫療公司 | Crispr/cas 組分之脂質奈米粒子調配物 |
| AU2017374044B2 (en) | 2016-12-08 | 2023-11-30 | Intellia Therapeutics, Inc. | Modified guide RNAs |
| AU2017379073B2 (en) | 2016-12-22 | 2023-12-14 | Intellia Therapeutics, Inc. | Compositions and methods for treating alpha-1 antitrypsin deficiency |
| AR113154A1 (es) | 2017-09-29 | 2020-01-29 | Intellia Therapeutics Inc | Polinucleótidos, composiciones y métodos para edición del genoma |
| JP7460643B2 (ja) * | 2018-10-16 | 2024-04-02 | ブルーアレル, エルエルシー | 遺伝子へのdnaの標的化挿入のための方法 |
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- 2019-10-18 CN CN201980082770.6A patent/CN113195721A/zh active Pending
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- 2019-10-18 JP JP2021521383A patent/JP2022505381A/ja active Pending
- 2019-10-18 SG SG11202103735TA patent/SG11202103735TA/en unknown
- 2019-10-18 MX MX2021004276A patent/MX2021004276A/es unknown
- 2019-10-18 US US16/657,967 patent/US20200270618A1/en active Pending
- 2019-10-18 EP EP19798480.0A patent/EP3867378A1/en active Pending
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| CN113195721A (zh) | 2021-07-30 |
| EP3867378A1 (en) | 2021-08-25 |
| SG11202103735TA (en) | 2021-05-28 |
| CA3116739A1 (en) | 2020-04-23 |
| BR112021007289A2 (pt) | 2021-07-27 |
| MX2021004276A (es) | 2021-09-08 |
| US20200270618A1 (en) | 2020-08-27 |
| JP2022505381A (ja) | 2022-01-14 |
| IL282237A (en) | 2021-05-31 |
| CO2021006367A2 (es) | 2021-08-19 |
| PH12021550842A1 (en) | 2021-12-06 |
| WO2020082047A1 (en) | 2020-04-23 |
| AU2019361204A1 (en) | 2021-05-27 |
| WO2020082047A8 (en) | 2024-11-07 |
| EA202191067A1 (ru) | 2021-11-17 |
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