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US009719087B2 a2) United States Patent (0) Patent No.: US 9,719,087 B2 Olson et al. (45) Date of Patent: *Aug. 1, 2017 (54) MICRO-RNA FAMILY THAT MODULATES A61LK 39/3955 (2013.01); AGLK 45/06 FIBROSIS AND USES THEREOF (2013.01); A6IL 31/08 (2013.01); AGIL 31/16 (2013.01); C12N 9/16 (2013.01); C12N (71) Applicant: THE BOARD OF REGENTS, THE 15/8509 (2013.01); AOIK 2207/30 (2013.01); UNIVERSITY OF TEXAS SYSTEM, AOIK 2217/052 (2013.01); AOLK 2217/075 Austin, TX (US) (2013.01); AOIK 2217/15 (2013.01); AOIK 2217/206 (2013.01); AOIK 2227/105 (72) Inventors: Erie N. Olson, Dallas, TX (US); Eva (2013.01); AOIK 2267/0375 (2013.01); AIL van Rooij, Utrecht (NL) 2300/258 (2013.01); A6IL 2300/45 (2013.01); : AOIL 2420/06 (2013.01); C12N 2310/113 (73) Assignee: THE BOARD OF REGENTS, THE (2013.01); CI2N 2310/141 (2013.01); CI2N UNIVERSITY OF TEXAS SYSTEM, 2310/315 (2013.01); C12N 2310/321 Austin, TX (US) (2013.01); C12N 2310/346 (2013.01); C12N (*) Notice: Subjectto any disclaimer, the termbe this (013.01ars orb01301CDN US.C.patent154(b)is extendedby 0 ordays.adjusted under 2320/32 (2013.01);4 . CI2N 2330/10yor(2013.01) (58) Field of Classification Search This patent is subject to a terminal dis- CPC vieceeceseeseeeeeeee C12N 15/113; C12N 2310/141 claimer. See application file for complete search history. — (21) Appl. No.: 14/592,699 (56) References Cited (22) Filed: Jan. 8, 2015 U.S. PATENT DOCUMENTS (65) Prior Publication Data 7,232,806 B2 6/2007 Tuschlet al. US 2016/0145608 Al May 26, 2016 7,674,617 B2 3/2010 Kim etal. 8,440,636 B2* 5/2013 Olson wu... AOIK 67/0276 Related U.S. Application Data 514/44 A 8,940,711 B2 1/2015 Olsonet al. (60) Division of application No. 13/840,823, filed on Mar. 8,940,712 B2 1/2015 Olsonetal. 15, 2013, now Pat. No. 8,940,712, which is a (Continued) continuation of application No. 12/671,445, filed as application No. PCT/US2008/071839 on Jul. 31, FOREIGN PATENT DOCUMENTS 2008, now Pat. No. 8,440,636. EP 1440981 42 7/2004 (60) Provisional application No. 61/047,014,filed on Apr. EP 1627925 Al 2/2006 22, 2008, provisional application No. 60/980,303, (Continued) filed on Oct. 16, 2007, provisional application No. 60/952,917, filed on Jul. 31, 2007. OTHER PUBLICATIONS (51) Int. Cl. Van Rooij et al. “Control of Stress-Dependent Cardiac Growth and CIQN 15/113 (2010.01) Gene Expression by a MicroRNA”, Science, Apr. 27, 2007, vol. AOIK 67/027 (2006.01) 316, Issue 5824, p. 575-579. AGIK 38/22 (2006.01) (Continued) CI2N Y16 (2006.01) CI2N 15/85 (2006.01) AGIK 31/7105 (2006.01) Primary Examiner — J. E. Angell AGIK 31/712 (2006.01) AGIK 31/7125 (2006.01) AGIK 31/713 (2006.01) 6) ABSTRACT A6IK 39/395 (2006.01) The present invention relates to the identification of a AGIK 45/06 (2006.01) microRNA family, designated miR-29a-c, that is a key A6IK 31/07 (2006.01) regulator of fibrosis in cardiac tissue. The inventors show AGIK 31/355 (2006.01) that members of the miR-29 family are down-regulated in A6IK 31/375 (2006.01) the heart tissue in responseto stress, and are up-regulated in AGIL 31/08 (2006.01) heart tissue of mice that are resistant to both stress and AGIL 31/16 (2006.01) fibrosis. Also provided are methods of modulating expres- (52) U.S. Cl. sion and activity of the miR-29 family of miRNAs as a CPC we CI2N 15/113 (2013.01); AOLK 67/0276 treatmentfor fibrotic disease, including cardiac hypertrophy, (2013.01); A61K 31/07 (2013.01); A6IK skeletal muscle fibrosis other fibrosis related diseases and 31/355 (2013.01); A6IK 31/375 (2013.01); collagen loss-related disease. AGIK 31/712 (2013.01); A6IK 31/713 (2013.01); A61K 31/7105 (2013.01); A6IK 31/7125 (2013.01); A6LK 38/2242 (2013.01); 22 Claims, 29 Drawing Sheets US 9,719,087 B2 Page 2 (56) References Cited WO WO 2007/081720 A2 7/2007 WO WO 2007/081740 A2 7/2007 U.S. PATENT DOCUMENTS WO WO 2007/109236 A2 9/2007 WO WO 2007/112754 A2 10/2007 — 8,940,713 B2 1/2015 Olson et al. WO WO 2008/016924 A2 2/2008 9,376,681 B2 6/2016 Montgomery etal. WO WO 2008/043521 A2 4/2008 2005/0059005 Al 3/2005 Tuschl etal. WO WO 2008/061537 A2 5/2008 2005/0222399 Al 10/2005 Bentwich WO WO 2008/116267 Al 10/2008 — 2005/0261218 Al 11/2005 Esau etal. WO WO 2008/147839 Al 12/2008 — 2006/00 19286 Al 1/2006 Horvitz et al. WO WO 2009/012263 A2 1/2009 2006/0063730 Al 3/2006 Moniaetal. WO WO 2009/026576 Al 2/2009 2006/0105360 Al 5/2006 Croceet al. WO WO 2009/043353 A2 4/2009 2006/0185027 Al 8/2006 Bartel et al. WO WO 2009/058818 A2 5/2009 2006/0247 193 Al 11/2006 Taira et al. WO WO 2009/062169 A2 5/2009 2007/0087335 Al 4/2007 Brahmachariet al. WO WO 2009/111375 A2 9/2009 2007/0092882 Al 4/2007 Wangetal. WO WO 2009/114681 A2 9/2009 2008/0050722 Al 2/2008 Kim etal. WO WO 2009/121031 Al 10/2009 — 2008/0176766 Al 7/2008 Brownetal. WO WO 2009/149182 Al 12/2009 — 2009/0053718 Al 2/2009 Naguibnevaet al. WO WO 2010/036939 A2 4/2010 2009/0092980 Al 4/2009 Arenzet al. WO WO 2010/048585 A2 4/2010 2009/0143326 Al 6/2009 Obadetal. 2009/028 1167 Al 11/2009 Shenetal. OTHER PUBLICATIONS 2009/0286969 Al 11/2009 Esau etal. 2009/029 1906 Al 11/2009 Esau etal. Chenget al., “MicroRNAs Are Aberrantly Expressed. in Hypertro- 2009/029 1907 Al 11/2009 Esau etal. phic Heart,” Am. J. Pathol. 170(6):1831-1840 (2007). 2009/0293 148 Al 11/2009 Ren etal. Kim, “International Search Report,” 4 pages, from International 2009/03 17369 Al 12/2009 Hosodaetal. Patent Appl. No. PCT/US2008/071839, Korean Intellectual Prop- 2009/0326049 Al 12/2009 Aristarkhovetal. 2010/0029003 Al 2/2010 Bartel et al. erty Office, Daejon, Republic of Korea (mailed Jan. 6, 2009). Rooij et al., “A signature pattern of stress-responsive microRNAs 2010/00875 12 4/2010 Tuschl etal. that can evoke cardiac hypertrophy and heart failure,” Proc. Natl. 2010/00875 13 4/2010 Tuschl etal. 2010/0093837 4/2010 Tuschl etal. Acad. Sci. USA 103(48): 18255-18260 (2006). 2010/0099748 4/2010 Tuschl etal. Tatsuguchi et al., “Expression of MicroRNAs is Dynamically 2010/0113561 5/2010 Tuschl etal. Regulated During Cardiomyocyte Hypertrophy,” J. Mol. Cell. 2016/0145607 5/2016 Olson et al. Cardiol. 42(6):1137-1141 (2007). 2016/0145609 5/2016 Olson et al. Lagos-Quintanaet al., “New microRNAsfrom mouse and human,” 2016/0355815 12/2016 Montgomery etal. RNA,vol. 9:175-179, 2003. Lagos-Quintanaet al., “Identification of tissue-specific microRNAs FOREIGN PATENT DOCUMENTS from mouse,” Current Biology, vol. 12:735-739, 2002. Sempere et al., “Expression profiling of mammalian microRNAs EP 1777301 A2 4/2007 uncovers a subset of brain-expressed microRNAs with possible EP 1959012 A2 8/2008 roles in murine and human neuronal differentiation,” Genome EP 2113567 Al 11/2009 Biology, vol. 5:R13, 2004. JP 2006-5 19008 8/2006 Mott et al., “miR-29 regulates Mcl-1 protein expression and. JP 2006-292367 10/2006 apoptosis,” Oncogene, vol. 26: 6133-6140, 2007. WO WO 03/029459 A2 4/2003 Heet al., “Overexpression of Micro Ribonucleic Acid 29, Highly WO WO 2004/076622 A2 9/2004 Up-Regulated in Diabetic Rats, Leads to Insulin Resistance in WO WO 2005/013901 A2 2/2005 3T3-L1 Adipocytes,” Molecular Endocrinology, vol. 21: 2785- WO WO 2005/017145 Al 2/2005 2794, 2007. WO WO 2005/040419 Al 5/2005 Zhaoet al., “Dysregulation of Cardiogenesis, Cardiac Conduction, WO WO 2005/047505 A2 5/2005 WO WO 2005/056797 Al 6/2005 and Cell Cycle in Mice Lacking miRNA-1-2,” Cell, vol. 129: WO WO 2005/118806 A2 12/2005 303-317, 2007. WO WO 2006/033020 A2 3/2006 Van Rooij et al., “Dysregulation of microRNAsafter myocardial WO WO 2006/033928 A2 3/2006 infarction reveals a role of miR-29 in cardiac fibrosis,” Proc. Natl. WO WO 2006/081284 A2 8/2006 Acad. Sci. USA, vol. 105: 13027-13032, 2008. WO WO 2006/108473 Al 10/2006 Spindler, Supplementary European Search Report for European WO WO2006/111512 Al 10/2006 Application No. 08797006.7, 10 pages, European Patent Office, The WO WO 2006/128245 Al 12/2006 Hague, mailed Aug. 17, 2011. WO WO 2006/133022 A2 12/2006 Pekarsky Y. et al., “Tell expression in chronic lymphocytic leukemia WO WO 2006/137941 A2 12/2006 is regulated by miR-29 and miR-181,” Cancer Research, vol. WO WO 2007/000668 A2 1/2007 66:11590-11593, 2006. WO WO 2007/016548 A2 2/2007 WO WO 2007/033023 A2 3/2007 Written Opinion of the International Searching Authority mailed on WO WO 2007/042899 A2 4/2007 Jan. 6, 2009, for PCT Application No. PCT/US2008/071839, filed. WO WO 2007/067695 A2 6/2007 on Jul. 31, 2008, 5 pages. WO WO 2007/070483 A2 6/2007 WO WO 2007/081680 A2 7/2007 * cited by examiner B2 9,719,087 US t “Sig if DONNODYVYWWOSYpOVOTEAY JS QOS-HIW GIMBW (s :oN ar a5) 1.2 wou ¥ a.
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  • Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding

    Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding

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