ES2610622T3 - Regulación de microARN miR-33 en el tratamiento de trastornos relacionados con colesterol - Google Patents
Regulación de microARN miR-33 en el tratamiento de trastornos relacionados con colesterol Download PDFInfo
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- ES2610622T3 ES2610622T3 ES10764855.2T ES10764855T ES2610622T3 ES 2610622 T3 ES2610622 T3 ES 2610622T3 ES 10764855 T ES10764855 T ES 10764855T ES 2610622 T3 ES2610622 T3 ES 2610622T3
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- C12N2310/32—Chemical structure of the sugar
- C12N2310/323—Chemical structure of the sugar modified ring structure
- C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
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Abstract
Un ácido nucleico que es complementario de las SEQ ID NO. 1 o 2, para uso en el tratamiento terapéutico de un sujeto que necesite homeostasis de colesterol reduciendo la cantidad de colesterol en circulación en la sangre del sujeto; o aumentando la salida de colesterol intracelular y/o la producción de HDL en el hígado del sujeto.
Description
análisis por FPLC de suero agrupado como se ha descrito (Hyogo H, et al. (2002) J. Biol. Chem. 277: 34117). Las concentraciones de colesterol HDL en plasma aumentaron significativamente en animales tratados con LNAantisentido de miR33a en comparación con ratones tratados con controlLNA (Fig. 10A, B y Tabla 2). Por el contrario, no hubo ningún efecto significativo en las concentraciones en plasma de colesterol LDL, triglicéridos o niveles de
5 glucosa (Fig. 10BD y Tabla 2). En estos experimentos, tampoco hubo ninguna hepatotoxicidad aparente (AST/ALT en plasma) (Fig. 10E, F y Tabla 2). La elevación observada en HDL en plasma colesterol en respuesta a tratamiento con antisentido de LNAmiR33a es coherente con la regulación de la salida de colesterol dependiente de ABCA1 por miR33a in vivo.
10 Estos resultados confirman adicionalmente que la familia de SREBP de mamífero de factores de transcripción, reguladores clave de genes colesterogénicos y lipogénicos, son hospedadores para miARN conservados (miR33a/b) que actúan en concierto con los productos génicos de hospedador de SREBP para gobernar los niveles de colesterol intracelular y homeostasis de colesterol en vertebrados. La Fig. 10G representa un modelo para regulación coordinada de homeostasis de colesterol por miR33 y su producto génico hospedador SREBP. miR33 reprime la traducción de
15 ABCA1 dirigiéndose a su 3’ UTR. Esta etapa está coordinada con la expresión de SREBP, que activa la biosíntesis de colesterol y captación mediante transactivación de genes colesterogénicos. La acumulación de colesterol inhibe la ruta de SREBP, y activa la expresión de ABCA1, que se trasloca a la membrana celular y media en la salida de colesterol a apoAI y HDL.
20 Tabla 2
- n
- Tratamiento Colesterol [mg/dl] triglicéridos [mg/dl] Glucosa [mg/dl] ALT [UI/l] AST [UI/l]
- antes
- después antes después antes después antes después antes después
- 1
- PBS 163,5 167 211 211 159 318 17 68 58 101
- 2
- PBS 239,5 209 372 195 193 333 16 33 39 27
- 3
- PBS 190,5 220 141 256 226 329 37 10 35 135
- 4
- PBS 230 222 257 171 186 378 14 25 44 289
- 5
- PBS 189,5 205 263 161 201 282 52 14 39 135
- 1
- LNA 243 325 249 236 214 26 17 60 67
- 2
- LNA 188 204 329 193 216 421 46 61 37 209
- 3
- LNA 234,5 264 278 283 264 264 44 23 68 44
- 4
- LNA 239 247 486 204 218 391 35 35 63 33
- 5
- LNA 215,5 280 289 133 158 230 28 33 153 229
- 1
- LC 206 157 308 224 275 72 26 128 142
- 2
- LC 214,5 224 243 241 390 365 21 22 30 71
- 3
- LC 180 223 384 134 160 233 18 22 54 150
- 4
- LC 201 206 197 167 233 416 26 15 67 46
- 5
- LC 210 186 238 373 286 299 47 17 68 52
Tabla 2. Tratamiento de ratones con una dieta de tipo occidental con ácido nucleico bloqueado (LNA)antímero de miR33a. Se midieron colesterol en suero total (A), triglicéridos en plasma (B), glucosa (C), AST (D) y ALT (E) en ratones alimentados con una dieta de tipo occidental antes y después de la inyección con PBS (vehículo),
25 oligonucleótidos antisentidoLNA dirigidos contra miR33a de ratón y oligonucleótidos de control de LNA mezclados (LC).
Como se representa en estos ejemplos, miembros de la familia de SREBP de mamífero de factores de transcripción, reguladores clave de genes colesterogénicos y lipogénicos, son hospedadores de miARN conservados (miR33a/b)
30 que actúan en concierto con los productos génicos hospedadores de SREBP para gobernar los niveles de colesterol intracelular y homeostasis de colesterol en vertebrados. miR33 ejerce control postranscripcional del transportador de colesterol ABCA1, con importantes consecuencias para el tráfico de colesterol in vitro y síntesis de HDL in vivo.
16
Claims (1)
-
imagen1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16504109P | 2009-03-31 | 2009-03-31 | |
| US165041P | 2009-03-31 | ||
| PCT/US2010/029376 WO2010120508A2 (en) | 2009-03-31 | 2010-03-31 | Regulation of mir-33 micrornas in the treatment of cholesterol-related disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2610622T3 true ES2610622T3 (es) | 2017-04-28 |
Family
ID=42983071
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES10764855.2T Active ES2610622T3 (es) | 2009-03-31 | 2010-03-31 | Regulación de microARN miR-33 en el tratamiento de trastornos relacionados con colesterol |
Country Status (6)
| Country | Link |
|---|---|
| US (3) | US20120053229A1 (es) |
| EP (1) | EP2414521B1 (es) |
| JP (1) | JP5753838B2 (es) |
| DK (1) | DK2414521T3 (es) |
| ES (1) | ES2610622T3 (es) |
| WO (1) | WO2010120508A2 (es) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7683036B2 (en) | 2003-07-31 | 2010-03-23 | Regulus Therapeutics Inc. | Oligomeric compounds and compositions for use in modulation of small non-coding RNAs |
| CN103223177B (zh) * | 2009-05-06 | 2016-08-10 | 库尔纳公司 | 通过针对脂质转运和代谢基因的天然反义转录物的抑制治疗脂质转运和代谢基因相关疾病 |
| US20110281933A1 (en) * | 2010-05-13 | 2011-11-17 | Saint Louis University | Methods and compositions for the management of cardiovascular disease with oligonucleotides |
| JP2012019728A (ja) * | 2010-07-14 | 2012-02-02 | Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho | ヒトabca1遺伝子の転写を調整する作用を有する物質のスクリーニング方法 |
| CA2808889A1 (en) * | 2010-08-27 | 2012-03-01 | New York University | Mir-33 inhibitors and uses thereof |
| WO2012069059A1 (en) | 2010-11-23 | 2012-05-31 | Mirrx Therapeutics A/S | Oligonucleotides for modulation of target rna activity |
| EP2663323B1 (en) | 2011-01-14 | 2017-08-16 | The General Hospital Corporation | Methods targeting mir-128 for regulating cholesterol/lipid metabolism |
| US9241950B2 (en) | 2011-04-28 | 2016-01-26 | New York University | MiR-33 inhibitors and uses thereof to decrease inflammation |
| US20150315595A1 (en) * | 2012-03-12 | 2015-11-05 | Santaris Pharma A/S | Compositions and Methods for Modulation of ATXN3 Expression |
| WO2014012047A1 (en) * | 2012-07-12 | 2014-01-16 | University Of Louisville Research Foundation, Inc. | Systems and methods for diagnosis, prognosis, and treatment of cancer |
| CN104837996A (zh) | 2012-11-15 | 2015-08-12 | 罗氏创新中心哥本哈根有限公司 | 抗apob反义缀合物化合物 |
| AU2014211406B2 (en) | 2013-01-30 | 2019-07-18 | Roche Innovation Center Copenhagen A/S | LNA oligonucleotide carbohydrate conjugates |
| EP3104896B1 (en) | 2014-02-14 | 2019-10-09 | The Children's Hospital of Philadelphia | Compositions and methods for treatment of cholestasis |
| JP6666002B2 (ja) | 2015-10-07 | 2020-03-13 | 国立大学法人京都大学 | Tdp−43プロテノパシーの予防又は治療用組成物 |
| WO2021177267A1 (ja) * | 2020-03-02 | 2021-09-10 | 田辺三菱製薬株式会社 | miR-33b阻害物質による動脈瘤の予防または治療 |
| EP4333907A4 (en) * | 2021-05-07 | 2025-05-21 | The Regents of the University of California | Mirna inhibitors for preventing and treating aneurysms, hypertension, ards and other diseases associated with endothelial dysfunction |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60035163T2 (de) * | 1999-03-15 | 2008-02-21 | University Of British Columbia, Vancouver | Abc1 polypeptide und verfahren und reagenzien zur modulation des cholesterolgehalts |
| CN100513570C (zh) * | 1999-06-18 | 2009-07-15 | Cv治疗公司 | 结合框运输蛋白abc1的调节作用 |
| US6835563B1 (en) * | 1999-06-18 | 2004-12-28 | Cv Therapeutics | Compositions and methods for increasing cholesterol efflux and raising HDL ATP binding cassette transporter protein ABC1 |
| EP1407774A1 (en) * | 2002-09-10 | 2004-04-14 | LION Bioscience AG | 2-Amino-4-quinazolinones as LXR nuclear receptor binding compounds |
| EP1791567B1 (en) * | 2004-08-10 | 2015-07-29 | Alnylam Pharmaceuticals Inc. | Chemically modified oligonucleotides |
| CA2584331A1 (en) * | 2004-10-22 | 2006-05-04 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for modulating pgc-1.beta. to treat lipid-related diseases and disorders |
| AU2006279906B2 (en) * | 2005-08-10 | 2012-05-10 | Alnylam Pharmaceuticals, Inc. | Chemically modified oligonucleotides for use in modulating micro RNA and uses thereof |
| JP2009507918A (ja) * | 2005-09-12 | 2009-02-26 | ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイション | Bcl2関連癌の診断及び療法のための組成物及び方法 |
| WO2007109350A2 (en) * | 2006-03-23 | 2007-09-27 | California Institute Of Technology | Modulation of innate immunity receptors' signaling by micrornas mir-146a and mir-146b |
| WO2008014008A2 (en) * | 2006-07-28 | 2008-01-31 | The Johns Hopkins University | Compositions and methods for modulating angiogenesis |
| EP2054529B1 (en) * | 2006-08-25 | 2014-03-26 | Duke University | Methods for in vivo identification of endogenous mrna targets of micrornas |
| US8673872B2 (en) * | 2006-08-28 | 2014-03-18 | The University Of Western Australia | Method of modulation of expression of epidermal growth factor receptor(EGFR) involving miRNA |
| AU2007323469B2 (en) * | 2006-11-23 | 2014-07-24 | Guangdong Maijinjia Biotechnology Co., Ltd | Oligonucleotides for modulating target RNA activity |
| US20090005336A1 (en) * | 2007-05-08 | 2009-01-01 | Zhiguo Wang | Use of the microRNA miR-1 for the treatment, prevention, and diagnosis of cardiac conditions |
| WO2008142567A2 (en) * | 2007-05-18 | 2008-11-27 | Karolinska Institutet Innovations Ab | Microrna molecules associated with inflammatory skin disorders |
| US20090082297A1 (en) * | 2007-06-25 | 2009-03-26 | Lioy Daniel T | Compositions and Methods for Regulating Gene Expression |
| EP2182969B1 (en) * | 2007-07-31 | 2016-11-16 | The Board of Regents of The University of Texas System | A micro-rna family that modulates fibrosis and uses thereof |
| US7812003B2 (en) * | 2007-08-02 | 2010-10-12 | Safe Stephen H | Antisense microRNA and uses therefor |
| CA2716343A1 (en) * | 2008-02-21 | 2009-08-27 | The Board Of Regents Of The University Of Texas System | Micro-rnas that modulate smooth muscle proliferation and differentiation and uses thereof |
| EP2297338A2 (en) * | 2008-05-30 | 2011-03-23 | Ordway Research Institute, Inc. | Methods for disease therapy |
-
2010
- 2010-03-31 EP EP10764855.2A patent/EP2414521B1/en active Active
- 2010-03-31 WO PCT/US2010/029376 patent/WO2010120508A2/en not_active Ceased
- 2010-03-31 DK DK10764855.2T patent/DK2414521T3/en active
- 2010-03-31 JP JP2012503656A patent/JP5753838B2/ja active Active
- 2010-03-31 ES ES10764855.2T patent/ES2610622T3/es active Active
- 2010-03-31 US US13/262,083 patent/US20120053229A1/en not_active Abandoned
-
2016
- 2016-10-27 US US15/335,699 patent/US20170233730A1/en not_active Abandoned
-
2017
- 2017-11-21 US US15/819,212 patent/US20180119148A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP2414521A2 (en) | 2012-02-08 |
| US20180119148A1 (en) | 2018-05-03 |
| JP5753838B2 (ja) | 2015-07-22 |
| WO2010120508A2 (en) | 2010-10-21 |
| EP2414521A4 (en) | 2013-02-13 |
| EP2414521B1 (en) | 2016-10-26 |
| WO2010120508A3 (en) | 2011-03-17 |
| DK2414521T3 (en) | 2017-01-30 |
| JP2012522509A (ja) | 2012-09-27 |
| US20120053229A1 (en) | 2012-03-01 |
| US20170233730A1 (en) | 2017-08-17 |
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