US008940712B2 a2) United States Patent (0) Patent No.: US 8,940,712 B2 Olsonet al. (45) Date of Patent: Jan. 27, 2015 (54) MICRO-RNA FAMILY THAT MODULATES 2310/141 (2013.01); CI2N 2310/315 (2013.01); FIBROSIS AND USES THEREOF C1I2N 2310/321 (2013.01); C12N 2310/346 (2013.01); CI2N 2310/3515 (2013.01); C12N (71) Applicant: The Board of Regents, The University 2320/31 (2013.01); C12N 2330/10 (2013.01) of Texas System,Austin, TX (US) USPC. ecsscssssssseesstvesnssnssresnesvesveecee 514/44 A (72) Inventors: Eric N. Olson, Dallas, TX (US); Eva (58) Field of Classification Search van Rooij, Utrecht (NL) USPC ooceecccccsscsecseeseeseeseeseeseeseesseeeeeeesneseees 514/44 A See application file for complete search history. (73) Assignee: The Board of Regents, The University of Texas System, Austin, TX (US) (56) References Cited (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S. PATENT DOCUMENTS U.S.C. 154(6)by I day. 7,232,806 B2 6/2007 Tuschlet al. 7,674,617 B2 3/2010 Kimetal. (21) Appl. No.: 13/840,823 2005/0059005 Al 3/2005 Tuschlet al. 2005/0222399 Al 10/2005 Bentwich (22) Filed: Mar. 15, 2013 2005/0261218 Al 11/2005 Esau etal. 2006/0019286 Al 1/2006 Horvitz et al. (65) Prior Publication Data 2006/0105360 Al 5/2006 Croceet al. 2006/0185027 Al 8/2006 Bartelet al. US 2013/0195891 Al Aug. 1, 2013 2006/0247193 Al 11/2006 Taira etal. 2007/0087335 Al 4/2007 Brahmachari etal. 2007/0092882 Al 4/2007 Wangetal. 2008/0176766 Al 7/2008 Brownetal. (63) Continuation of application No. 12/671,445, filed as 2009/0053718 Al 2/2009 Naguibnevaetal. application No. PCT/US2008/071839 on Jul. 31, sooOaaaoe ‘i eons One "a 2008, now Pat. No. 8,440,636. 2009/0281167 Al 11/2009 Shenad.et&al. (60) Provisional application No. 61/047,014, filed on Apr. (Continued) 22, 2008, provisional application No. 60/980,303, filed on Oct. 16, 2007, provisional application No. FOREIGN PATENT DOCUMENTS 60/952,917,filed on Jul. 31, 2007. EP 1440981 A2 7/2004 (51) Int. Cl. EP 1627925 Al 2/2006 CI2N 15/11 (2006.01) (Continued) A6I1K 31/713 (2006.01) AOIK 67/027 (2006.01) OTHER PUBLICATIONS A61K 38/22 (2006.01) CI2N 9/16 (2006.01) Cheng et al., “MicroRNAs Are Aberrantly Expressed in CIQN 15/113 (2010.01) Hypertrophic Heart,’ Am. J. Pathol. 170(6):1831-1840 (2007). CI2QN 15/85 (2006.01) (Continued) AG6IK 31/7105 (2006.01) A6I1K 31/712 (2006.01) AG6IK 31/7125 2006.01 AGIK 39/395 (3006 01) Primary Examiner — J. E. Angell AG6IK 45/06 (2006.01) (74) Altorney, Agent, or Firm — Cooley LLP A61K 31/07 (2006.01) A6IK 31/355 (2006.01) A6I1K 31/375 (2006.01) (67) ABSTRACT (52) U.S. Cl. The present invention relates to the identification of a CPC wee A61K 31/713 (2013.01); AOLK 67/0276 microRNA family, designated miR-29a-c, that is a key regu- (2013.01); A6LK 38/2242 (2013.01); C12N lator of fibrosis in cardiac tissue. The inventors show that 9/16 (2013.01); CI2N 15/113 (2013.01); CI2N members of the miR-29 family are down-regulated in the 15/8509 (2013.01); AGLK 31/7105 (2013.01); heart tissue in responseto stress, and are up-regulatedin heart A61LK 31/712 (2013.01); A6LK 31/7125 tissue of mice that are resistant to both stress and fibrosis. (2013.01); A6LK 39/3955 (2013.01); A61K Also provided are methods of modulating expression and 45/06 (2013.01); A61K 31/07 (2013.01); A6LK activity of the miR-29 family of miRNAsas a treatment for 31/355 (2013.01); A6LK 31/375 (2013.01); fibrotic disease, including cardiac hypertrophy, skeletal AOLK 2207/30 (2013.01); AOLK 2217/052 muscle fibrosis other fibrosis related diseases and collagen (2013.01); AOLK 2217/075 (2013.01); AOILK loss-related disease. 2217/15 (2013.01); AOLK 2217/206 (2013.01); AOLK 2227/105 (2013.01); AOLK 2267/0375 (2013.01); CI2N 2310/113 (2013.01); C12N 16 Claims, 25 Drawing Sheets US 8,940,712 B2 Page 2 (56) References Cited WO WO2008/061537 A2 5/2008 Wo WO 2008/116267 Al 10/2008 U.S. PATENT DOCUMENTS Wo WO 2008/147839 Al 12/2008 — Wo WO 2009/012263 A2 1/2009 2009/0286969 Al 11/2009 Esauetal. WO WO 2009/026576 Al 2/2009 2009/0291906 Al 11/2009 Esauetal. WO WO 2009/043353 A2 4/2009 2009/0291907 Al 11/2009 Esauetal. 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