US009078919B2 a2) United States Patent (0) Patent No.: US 9,078,919 B2 Olsonet al. (45) Date of Patent: *Jul. 14, 2015 (54) MICRO-RNAS OF THE MIR-15 FAMILY 2005/0182011 Al 8/2005 Olson etal. MODULATE CARDIOMYOCYTE SURVIVAL 2006/0058266 Al 3/2006 Manoharan etal. AND CARDIAC REPAIR 2006/0105360 Al 5/2006 Croce etal. 2006/0165659 Al 7/2006 Croceet al. 2006/0185027 Al 8/2006 Bartelet al. (71) Applicant: The Board of Regents, The University 2006/0189557 Al 8/2006 Slack et al. of Texas System, Austin, TX (US) 2006/0247193 Al 11/2006 Taira et al. 2006/0252722 Al 11/2006 Lollo et al. (72) Inventors: Eric N. Olson, Dallas, TX (US); Eva 2007/0026403 Al 2/2007 Hatzigeorgiouetal. 2007/0054287 Al 3/2007 Bloch van Rooij, Utrecht (NL) 2007/0213292 Al 9/2007 Stoffel et al. 2007/0259827 Al 11/2007 Aronin et al. (73) Assignee: The Board of Regents, the University 2007/0287179 Al 12/2007 Tuschletal. of Texas System, Austin, TX (US) 2007/0292878 Al 12/2007 Raymond. 2008/0050744 Al 2/2008 Brownetal. (*) Notice: Subject to any disclaimer, the term of this 2008/0176766 Al 7/2008 Brownetal. 2008/0220423 Al 9/2008 Molleret al. patent is extended or adjusted under 35 2009/0053718 Al 2/2009 Naguibnevaetal. U.S.C. 154(b) by 0 days. 2009/0092980 Al 4/2009 Arenzet al. 2009/0131356 Al 5/2009 Baderet al. This patent is subject to a terminal dis- 2009/0176723 Al 7/2009 Brownetal. claimer. 2009/0214477 Al 8/2009 Betzet al. 2009/0221685 Al 9/2009 Esauetal. (21) Appl. No.: 13/970,379 2009/0226528 Al 9/2009 Czechet al. 2009/0281167 Al 11/2009 Shenetal. (22) Filed: Aug. 19, 2013 2009/0286969 Al 11/2009 Esauet al. 2009/0286973 Al 11/2009 Manoharan etal. 2009/0291906 Al 11/2009 Esauet al. (65) Prior Publication Data 2009/0291907 Al 11/2009 Esauet al. US 2014/0051745 Al Feb. 20, 2014 2009/0293148 Al 11/2009 Renetal. 2009/0298174 Al 12/2009 Esauet al. 2009/0306181 Al 12/2009 Ikedaet al. 2009/0326049 Al 12/2009 Aristarkhovet al. Related U.S. Application Data 2010/0029003 Al 2/2010 Bartel et al. 2010/0069471 Al 3/2010 Manoharan etal. (63) Continuation of application No. 12/742,233, filed as 2010/0087512 Al 4/2010 Tuschletal. application No. PCT/US2008/083020 on Nov. 10, 2010/0087513 Al 4/2010 Tuschletal. 2008, now Pat. No. 8,513,209. (Continued) (60) Provisional application No. 60/986,798,filed on Nov. 9, 2007. FOREIGN PATENT DOCUMENTS (51) Int. Cl. EP 1627925 Al 2/2006 AG6IK 48/00 (2006.01) EP 1676914 Al 7/2006 AGIK 45/06 (2006.01) (Continued) AOIK 67/027 (2006.01) CIIN 15/113 (2010.01) OTHER PUBLICATIONS AGIK 31/7105 (2006.01) (52) U.S.C Young, “International Search Report,” 4 pages, from International CPC veeceseseeee A61K 45/06 (2013.01); AOLK 67/0275 Patent Application No. PCT/US08/83020, USPTO, Alexandria, Vir- (2013.01); A6LK 31/7105 (2013.01); C12N ginia, US (mailed May 13, 2009). 15/113 (2013.01); AOLK 2207/05 (2013.01); (Continued) AOLK 2217/058 (2013.01); AOLK 2227/105 (2013.01); AOLK 2267/0375 (2013.01); C12N 2310/113 (2013.01); CI2N 2310/14 (2013.01); Primary Examiner — Kimberly Chong C12N 2330/10 (2013.01); C12N 2830/008 (2013.01) (74) Attorney, Agent, or Firm — Cooley LLP (58) Field of Classification Search None (57) ABSTRACT See application file for complete search history. A family of microRNAs, called the miR-15 family, which (56) References Cited includes miR-195, are shown to be up-regulated during U.S. PATENT DOCUMENTS pathological cardiac remodeling and repress the expression of mRNAsrequired for cell proliferation and survival, with 7,232,806 B2 6/2007 Tuschletal. consequent loss of cardiomyocytes. Strategies to block 7,482,117 B2 1/2009 Cargill et al. expression ofthe miR-15 family in the heart as a treatment for 7,582,744 B2 9/2009 Manoharan et al. diverse cardiac disease are provided. 7,759,319 B2 7/2010 Lollo et al. 2005/0026169 Al 2/2005 Cargill et al. 2005/0059005 Al 3/2005 Tuschlet al. 2005/0075492 Al 4/2005 Chenetal. 18 Claims, 9 Drawing Sheets US 9,078,919 B2 Page 2 (56) References Cited WO WO2008/061537 A2 5/2008 WO _-WO 2008/073920 A2 —-6/2008 — U.S. PATENT DOCUMENTS WO WO 2008/073921 A2 6/2008 WO WO 2008/073922 A2 6/2008 2010/0093837 Al 4/2010 Tuschlet al. WO WO 2008/073923 A2 6/2008 —_ 2010/0099748 Al 4/2010 Tuschlet al. 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LE wah WG2L wel PE aoe wie LE RU SyMMCopageiianir: Patent U.S. U.S. Patent Jul. 14, 2015 Sheet 3 of 9 US 9,078,919 B2 A microRNAsignature of the hypertrophic heart Normal | Failing Fold miR-23 _ miR-24 1.5 miR-125b 1.3 miR-195 3.0 miR-199a 2.1 miR-214 1.6 Figure 2 U.S. Patent Jul. 14, 2015 Sheet 4 of 9 US 9,078,919 B2 € &&. &.8 we OS neo 8‘ x* SyYBOMA FZ SHAM O 3 PiQure B2 py aunbi4 Awa ‘Soc ae mean 2 smwom@ aL pus E | [ ann ot ceo [ ue o 9,078,919 | 1 L, US +3 ‘et ret ca PT 9 dNd S6l VNU q of 5 Sheet OL Be n 2 se) ame 2015 FRB 14, RR Jul.