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(12) United States Patent (10) Patent No.: US 8,088,914 B2 Stoffel Et Al USOO8088914B2 (12) United States Patent (10) Patent No.: US 8,088,914 B2 Stoffel et al. (45) Date of Patent: Jan. 3, 2012 (54) MICRORNA AND METHODS FOR W W39: A: 38 INHIBITING SAME WO WO2004.044123 A2 5, 2004 WO WO2004.04851 1 A2 6, 2004 (75) Inventors: Markus Stoffel, Zurich (CH); Matthew WO WO2005O13901 A2 2, 2005 N. Poy, New York, NY (US); Thomas WO WO2005079397 A2 9, 2005 H. Tuschl, New York, NY (US) WO WO2006 119266 A2 11/2006 OTHER PUBLICATIONS (73) Assignee: The Rockefeller University, New York, NY (US) U.S. Appl. No. 10/604,945, filed Aug. 27, 2003. U.S. Appl. No. 10/604,984, filed Aug. 29, 2003. Avavin et al., “The Small RNA Profile During Drosophila (*) Notice: Subject to any disclaimer, the term of this Melanogaster Development”. Developmental Cell, vol. 5, p. 337-350 patent is extended or adjusted under 35 (2003). U.S.C. 154(b) by 144 days. Beigelman et al., “Chemical Modification of Hammerhead Ribozymes'. The Journal of Biological Chemistry, vol. 270, No. 43. p. 25702-25708 (1995). (21) Appl. No.: 12/498,020 Liang et al., “Inhibitor RNA Blocks the Protein TranslationMediated 1-1. by Hepatitis C Virus Internal Ribosome Entry Site in Vivo”. World J. (22) Filed: Jul. 6, 2009 Gastroenterol, 10(5), p. 664-667 (2004). O O Amarzguioui. Mohammed, et al., “Tolerance for mutations and (65) Prior Publication Data chemical modifications in a siRNA'. Nucleic Acids Research 2003, 31(2):589-595. US 2009/0275729 A1 Nov. 5, 2009 Bartel, David P. “MicroRNAs. Genomics, Biogenesis, Mechanism, O O and Function’, Cell 2004, 116:281-297. Related U.S. Application Data Elbashir, SaydaM., et al., “Duplexes of 21-nucleotide RNAs mediate (62) Division of application No. 12/045,484, filed on Mar. RNA interference in cultured mammalian cells', Nature 2001, 10, 2008, now Pat. No. 7,585,969, which is a division Holen,''. Torgeir, et al., “Positional66TY - effects of short interfering RNAs of application No. 10/824,633, filed on Apr. 13, 2004, targeting the human coagulation trigger Tissue Factor'.s Nucleic now Pat. No. 7,365,058. Acids Research 2002, 30(8): 1757-1766. (51) Int. Cl Holen, Torgeir, et al., “Similar behaviour of single-strand and double Strand siRNAS Suggests they act through a common RNAi pathway'. C7H 2L/04 (2006.01) Nucleic Acids Research 2003, 31(9):2401-2407. C7H 2L/02 (2006.01) Howard, Ken, “Unlocking the money-making potential of RNAi'. A6 IK 4.8/00 (2006.01) Nature Biotechnology 2003, 21 (12): 1441-1446. (52) U.S. Cl. ..................... 536/24.5, 536/23.1536/243 Kurreck, Jens, "Antisense technologies Improvement through novel . • - s chemical modifications'. Eur, J. Biochem. 2003, 270: 1628-1644. 536/24.31; 536/24.33: 514/44 Meister, Gunter, et al., “Sequence-specific inhibition of microRNA (58) Field of Classification Search ............... ... ... None and siRNA-induced RNA silencing, RNA 2004, 10:544-550. See application file for complete search history. Nelson, Peter, et al., “The microRNA world: Small is mighty”, TRENDS in Biochemical Sciences 2003, 28(10):534-540. (56) References Cited Database EMBL (Online), Homo Sapiens Genomic Sequence Sur rounding Notl site, clone NR3-B07C, XP002451881 retrieved from U.S. PATENT DOCUMENTS EBI accession No. EMBL: AJ332626: 21/22 residues match SEQID 7,217,807 B2 5, 2007 Bentwich No. 1; Oct. 2001, abstract. 2002/0168633 A1 11/2002 Mabilat et al. Database EMBL (Online), NISC is08a05.wl Soares NMBP1 Mus 2003. O10441.0 A1 6, 2003 Mittmann Musculus cDNA clone Image: 4314537 5", mRNA sequence, 2003. O108923 A1 6, 2003 TuSchlet al. XPO0245 1882 retrieved from EBI accession No. EMBL: CB057718; 2003/O152950 A1 8, 2003 Garner et al. 22/22 residues match SEQID No. 3; Jan. 2003, abstract. 2003/0220263 A1 11/2003 Feder et al. Database EMBL (Online), CH4#001 G02T7 Canine Heart Normal 2003/0224380 A1 12/2003 Becker et al. ized CDNA Library in pBluescript Canis familaris CDNA clone 2004.0002432 A1 1/2004 Okuda et al. CH4#001 G02 5", mRNA sequence. XP002451883 retrieved from 2004.0005584 A1 1/2004 Cohen et al. 2005/0222067 A1 10, 2005 Pfeffer et al. EBI accession No. EMBL: BU751380: 22/22 residues match SEQID 2006, O16691.0 A1 7/2006 TuSchlet al. No. 4; Oct. 2002, abstract. 2006, O257851 A1 11, 2006 Bentwich 2007/0O39072 A1 2/2007 Khvorova et al. (Continued) 2007/0042381 A1 2/2007 Bentwich et al. 2007/0287.179 A1 12, 2007 TuSchlet al. Primary Examiner — Amy Bowman 2008.0114162 A1 5, 2008 Khvorova et al. (74) Attorney, Agent, or Firm — Hoffmann & Baron, LLP 2008. O188428 A1 8, 2008 Bentwich 2008/031821.0 A1 12/2008 Bentwich (57) ABSTRACT 2009/0275729 A1 11, 2009 Stoffel et al. The invention relates to isolated DNA or RNA molecules FOREIGN PATENT DOCUMENTS comprising at least ten contiguous bases having a sequence in EP 0855184 A1 7, 1998 a pancreatic islet microRNA. In another embodiment, the WO WOO140521 A2 6, 2001 WO WOO142493 A2 6, 2001 invention relates to isolated single stranded pancreatic islet WO WOO177384 A2 10/2001 microRNA molecules or anti-pancreatic islet microRNA WO WOO210185 A1 2, 2002 molecules. WO WOO222.809 A2 3, 2002 WO WOO3O29459 A2 4/2003 35 Claims, 11 Drawing Sheets US 8,088.914 B2 Page 2 OTHER PUBLICATIONS Wiebusch et al., “Inhibition of Human Cytomegalovirus Replication Berezikov et al., “Phylogenetic Shadowing and Computational Iden by Small Interfering RNAs'. Journal of General Virology, 85, p. 179-184 (2004). tification of Human MicroRNA Genes”. Cell, vol. 120, pp. 21-24 Vanitharani et al., “Short Interfering RNA-Mediated Interference of (2005). Gene Expression and Viral DNA Accumulation in Cultured Plant Seitz, et al., “A Large Imprinted MicroRNA Gene Cluster at the Cells”, PNAS, vol. 100, No. 16, p. 9632-9636 (2003). Mouse Elkl-Gtl2 Domain'. Genome Research, pp2. 1-8 (2004). Pfitzner et al., “Isolation and Characterization of cDNA Clones Cor Xie et al., “Systematic Discovery of Regulatory Motifs in Human responding to Transcripts from the BamHl H and F Regions of the Promoters and 3' UTR's by Comparison of Several Mammals'. Epstein-Barr Virus Genome'. Journal of Virology, vol. 61, No. 9, p. Nature, pp. 1-8 (2005). 2902-2909 (1987). Analysis and accompanying remarks by Rosetta Genomics of the Pfeffer et al., “Indentification of Virus-Encoded microRNAs'. Sci sequences presented in Table A2 of the specification of the instant ence, vol. 304, p. 734-736 (2004). application (Jun. 28, 2007). Zeng, et al., “MicroRNAs and Small Interfering RNAS Can Inhibit Table of information provided by Rosetta regarding the applications mRNA Expression by Similar Mechanisms”, PNAS, vol. 100, No. submitted in IDS dated Jul 12, 2007 (Jun. 28, 2007). 17, p. 9779-9784 (2003). Analysis by Rosetta of the sequences of Table A2 compared to those Boutla et al., “Developmental Defects by Antisense-Mediated Inac disclosed in Rosetta's patent applications (Jun. 28, 2007). tivation of Micr-RNAS 2 and 13 in Drosophila and the Identification AC 146999, Murphy et al. Oct. 31, 2003, p. 1-67. of Putative Target Genes', Nucleic Acids Research, vol. 31, No. 17. Murphy et al., "Coding Potential of Laboratory and Clinical Strains pp. 4973-4980 (2003). of Human Cytomegalovirus', PNAS, vol. 100, No. 25, p. 14976 Kawasaki et al., “Hes1 is a Target of MicroRNA-23 During Retinoic 14981 (2003). Acid-Induced Neutonal Differentiation of NT2 Cells', Nature, vol. Taliansky et al., “An Umbraviral Protein, Involved in Long-Distance 423, No. 6942, pp. 838-842 (2003). RNA Movement, Binds Viral RNA and Forms Unique, Protective Mourelatos et al., “MiRNPs: A Novel Class of Ribonucleoproteins Ribonucleoprotin Complexes”,Journal of Virology, vol. 77. No. 5, p. Containing Numerous microRNAs'. Genes and Development, vol. 3031-3040 (2003). 16, No. 6, pp. 720-728 (2002). Paddison et al., “Short Hairpin RNAs (shRNAs) Induce Sequence Hutvagner et al., “Sequence-Specific Inhibition of Small HRN func Specific Silencing in Mammalian Cells”. Genes & Development, tion”. PLOS Biology, Public Library of Science, vol. 2, No. 4, pp. 16:948-958 (2002). 465-475 (2004). U.S. Patent Jan. 3, 2012 Sheet 1 of 11 US 8,088,914 B2 O CH o--o O Phosphorothioate DNA Unit 2'-O-methyl RNA unit 2'-O-methoxy-ethyl RNA unit (PS) (OMe) (MOE) Structure 1 Structure 3 Structure 4 NH Peptide nucleic acid unit N3'-P5' Phosphoroamidate DNA unit 2'-fluoro-ribo nucleic acid unit (PNA) (NP) (FANA) Structure 6 Structure 2 Structure 7 N O O o= -o o=-N- O O Y. Y Locked nucleic acid unit Morpholino phosphoroamidate Cyclohexane nucleic acid unit (LNA) nucleic acid unit (CeNA) Structure 5 (MF) Structure 10 Structure 8 Tricyclonucleic acid unit Structure 9 U.S. Patent Jan. 3, 2012 Sheet 2 of 11 US 8,088,914 B2 Figure 2A C - A CCU C C GAC CC CGCG CGAGCC CG ACAAA CG C GG GUGC GCUCGG GC UGUUU GC U (SEQ. ID. NO. 31) C A - CUU U U GAG U.S. Patent Jan. 3, 2012 Sheet 3 of 11 US 8,088,914 B2 Figure 2B MIN6 Br Heart Liver Kid Adip Lung Spl Tes. S Int MiR-375 d miR-376 t-RNA U.S. Patent Jan. 3, 2012 Sheet 4 of 11 US 8,088,914 B2 Figure 2C Islet MN6 Pancreas 10 ug 10 ug l0 ug miR-375 t-RNA U.S. Patent Jan. 3, 2012 US 8,088,914 B2 Figure 3 c=bcaeococ-o siRNA-Luc si-Gok Si-375 U.S. Patent Jan. 3, 2012 Sheet 6 of 11 US 8,088,914 B2 Figure 3B etion U.S. Patent Jan. 3, 2012 Sheet 7 of 11 US 8,088,914 B2 Figure 4A and 4B B: O-Vti1A alar sun an ambeam B: C-TATA BP IB: ot-Mtpn N2A B: O-ATA BP Ad-eGFP Ad-375 U.S.
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