RU2667960C2 - Способы лечения диабета и/или улучшения выживания панкреатических островков после трансплантации - Google Patents
Способы лечения диабета и/или улучшения выживания панкреатических островков после трансплантации Download PDFInfo
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- RU2667960C2 RU2667960C2 RU2014146170A RU2014146170A RU2667960C2 RU 2667960 C2 RU2667960 C2 RU 2667960C2 RU 2014146170 A RU2014146170 A RU 2014146170A RU 2014146170 A RU2014146170 A RU 2014146170A RU 2667960 C2 RU2667960 C2 RU 2667960C2
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- seq
- smad7
- diabetes
- cells
- antisense oligonucleotide
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| US201261625904P | 2012-04-18 | 2012-04-18 | |
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| PCT/US2013/037150 WO2013158868A1 (en) | 2012-04-18 | 2013-04-18 | Methods of treating diabetes and/or promoting survival of pancreatic islets after transplantation |
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| ITRM20030149A1 (it) | 2003-04-02 | 2004-10-03 | Giuliani Spa | Oligonucleotidi (odn) antisenso per smad7 e loro usi in campo medico |
| RU2593939C2 (ru) | 2008-11-13 | 2016-08-10 | Ногра Фарма Лимитед | Антисмысловые композиции и способы их получения и применения |
| JP6389122B2 (ja) | 2011-09-15 | 2018-09-12 | ノグラ ファーマ リミテッド | 抗ｓｍａｄ７治療に対する応答性をモニターするための方法 |
| CN107252492A (zh) | 2012-04-18 | 2017-10-17 | 诺格尔制药有限公司 | 治疗糖尿病和/或促进胰岛移植后存活的方法 |
| US10006029B2 (en) | 2013-03-15 | 2018-06-26 | Nogra Pharma Limited | Methods of treating colorectal cancer |
| ES2704092T3 (es) * | 2014-04-30 | 2019-03-14 | Procter & Gamble | Composición limpiadora |
| AU2015257589A1 (en) | 2014-05-09 | 2016-11-24 | Nogra Pharma Limited | Methods for treating inflammatory bowel disease |
| EP3207136A1 (en) | 2014-10-17 | 2017-08-23 | Nogra Pharma Limited | Methods and compositions for treating a subject with a smad7 antisense oligonucleotide |
| EP3165593B1 (en) * | 2015-10-29 | 2019-01-23 | The Procter and Gamble Company | Liquid detergent composition |
| EP3162878A1 (en) * | 2015-10-29 | 2017-05-03 | The Procter and Gamble Company | Liquid detergent composition |
| EP3420082A4 (en) | 2016-02-23 | 2019-10-16 | Celgene Alpine Investment Company II, LLC | METHOD FOR THE TREATMENT OF DARM FIBROSIS USING SMAD7 INHIBITION |
| US11584935B2 (en) * | 2018-05-08 | 2023-02-21 | University Of Miami | Materials and methods for the delivery of therapeutic nucleic acids to tissues |
| WO2020232247A1 (en) | 2019-05-14 | 2020-11-19 | Provention Bio, Inc. | Methods and compositions for preventing type 1 diabetes |
| IL298999A (en) | 2020-06-11 | 2023-02-01 | Provention Bio Inc | Methods and compositions for the prevention of type 1 diabetes |
| JP2024520444A (ja) | 2021-05-24 | 2024-05-24 | プロヴェンション・バイオ・インコーポレイテッド | １型糖尿病を治療するための方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003037368A2 (en) * | 2001-11-02 | 2003-05-08 | Klinikum Der Universität Regensburg | Smad7 inhibitors for the treatment of cns diseases |
| WO2009129544A1 (en) * | 2008-04-18 | 2009-10-22 | Baxter International Inc. | Microsphere-based composition for preventing and/or reversing new-onset autoimmune diabetes |
| RU2434942C2 (ru) * | 2004-09-28 | 2011-11-27 | Кварк Фармасьютикалс, Инк. | Олигорибонуклеотиды и способы их применения для лечения острой почечной недостаточности и других заболеваний |
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| US6656475B1 (en) * | 1997-08-01 | 2003-12-02 | The Johns Hopkins University School Of Medicine | Growth differentiation factor receptors, agonists and antagonists thereof, and methods of using same |
| ITRM20030149A1 (it) | 2003-04-02 | 2004-10-03 | Giuliani Spa | Oligonucleotidi (odn) antisenso per smad7 e loro usi in campo medico |
| AU2004263830B2 (en) * | 2003-06-13 | 2008-12-18 | Alnylam Pharmaceuticals, Inc. | Double-stranded ribonucleic acid with increased effectiveness in an organism |
| ITRM20030393A1 (it) * | 2003-08-11 | 2005-02-12 | Giuliani Spa | Uso di oligonucleotidi (odn) antisenso per smad7 per il trattamento delle patologie mediate dal fattore di trascrizione nucleare nf-kb. |
| GB0326778D0 (en) * | 2003-11-18 | 2003-12-24 | Imp College Innovations Ltd | Biological materials and uses thereof |
| AU2005288522B2 (en) | 2004-09-28 | 2012-06-28 | Quark Pharmaceuticals, Inc. | Oligoribonucleotides and methods of use thereof for treatment of alopecia, acute renal failure and other diseases |
| WO2007039151A1 (en) * | 2005-09-28 | 2007-04-12 | Universität Zürich | Blockers of transforming growth factor beta and its receptors for the treatment of infectious diseases |
| RU2593939C2 (ru) * | 2008-11-13 | 2016-08-10 | Ногра Фарма Лимитед | Антисмысловые композиции и способы их получения и применения |
| JP6389122B2 (ja) | 2011-09-15 | 2018-09-12 | ノグラ ファーマ リミテッド | 抗ｓｍａｄ７治療に対する応答性をモニターするための方法 |
| CN107252492A (zh) | 2012-04-18 | 2017-10-17 | 诺格尔制药有限公司 | 治疗糖尿病和/或促进胰岛移植后存活的方法 |
| US10006029B2 (en) | 2013-03-15 | 2018-06-26 | Nogra Pharma Limited | Methods of treating colorectal cancer |
| AU2014229985B2 (en) | 2013-03-15 | 2018-12-13 | Nogra Pharma Limited | Methods of treating colorectal cancer |
| AU2015257589A1 (en) | 2014-05-09 | 2016-11-24 | Nogra Pharma Limited | Methods for treating inflammatory bowel disease |
| EP3213070A2 (en) | 2014-10-17 | 2017-09-06 | Nogra Pharma Limited | Methods for dosing and monitoring smad7 antisense oligonucleotide treatment using biomarker levels |
| EP3207136A1 (en) | 2014-10-17 | 2017-08-23 | Nogra Pharma Limited | Methods and compositions for treating a subject with a smad7 antisense oligonucleotide |
| CA3000569A1 (en) | 2015-09-30 | 2017-04-06 | Nogra Pharma Limited | Methods of using smad7 antisense oligonucleotides based on biomarker expression |
| WO2017144689A1 (en) | 2016-02-24 | 2017-08-31 | Nogra Pharma Limited | Methods of treating celiac disease using smad7 inhibition |
| WO2018122376A1 (en) | 2016-12-30 | 2018-07-05 | Nogra Pharma Limited | Compositions of smad7 antisense oligonucleotide and methods of treating or preventing psoriasis |
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2013
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003037368A2 (en) * | 2001-11-02 | 2003-05-08 | Klinikum Der Universität Regensburg | Smad7 inhibitors for the treatment of cns diseases |
| RU2434942C2 (ru) * | 2004-09-28 | 2011-11-27 | Кварк Фармасьютикалс, Инк. | Олигорибонуклеотиды и способы их применения для лечения острой почечной недостаточности и других заболеваний |
| WO2009129544A1 (en) * | 2008-04-18 | 2009-10-22 | Baxter International Inc. | Microsphere-based composition for preventing and/or reversing new-onset autoimmune diabetes |
Non-Patent Citations (3)
| Title |
|---|
| MIZOBUCHI T., et al., Differential expression of Smad7 transcripts identifies the CD4+CD45RChigh regulatory T cells that mediate type V collagen-induced tolerance to lung allografts.J Immunol. 2003 Aug 1;171(3):1140-7. * |
| MIZOBUCHI T., et al., Differential expression of Smad7 transcripts identifies the CD4+CD45RChigh regulatory T cells that mediate type V collagen-induced tolerance to lung allografts.J Immunol. 2003 Aug 1;171(3):1140-7. SMART NG., et al., Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus.PLoS Biol. 2006 Feb;4(2):e39. Epub 2006 Jan 31. * |
| SMART NG., et al., Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus.PLoS Biol. 2006 Feb;4(2):e39. Epub 2006 Jan 31. * |
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| AU2013249191B2 (en) | 2019-01-03 |
| MX2014012650A (es) | 2015-04-08 |
| CN104487574A (zh) | 2015-04-01 |
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| US20150315573A1 (en) | 2015-11-05 |
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| US10081809B2 (en) | 2018-09-25 |
| CN104487574B (zh) | 2017-07-07 |
| EP2839004B1 (en) | 2019-06-12 |
| EP2839004A1 (en) | 2015-02-25 |
| JP2015514778A (ja) | 2015-05-21 |
| JP6348484B2 (ja) | 2018-06-27 |
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| US20190136237A1 (en) | 2019-05-09 |
| WO2013158868A1 (en) | 2013-10-24 |
| JP2018131468A (ja) | 2018-08-23 |
| ES2732252T3 (es) | 2019-11-21 |
| US20200239884A1 (en) | 2020-07-30 |
| IN2014DN08158A (https=) | 2015-05-01 |
| NZ630914A (en) | 2017-01-27 |
| CA2870547A1 (en) | 2013-10-24 |
| DK2839004T3 (da) | 2019-07-01 |
| US10443056B2 (en) | 2019-10-15 |
| CN107252492A (zh) | 2017-10-17 |
| HK1207117A1 (en) | 2016-01-22 |
| MX370149B (es) | 2019-12-03 |
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