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(12) Patent Application Publication (10) Pub. No.: US 2016/0348103 A1 WHEELER Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0348103 A1 WHEELER Et Al US 201603481 03A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0348103 A1 WHEELER et al. (43) Pub. Date: Dec. 1, 2016 (54) OLIGONUCLEOTIDES AND METHODS FOR Related U.S. Application Data TREATMENT OF CARDIOMYOPATHY USING RNA INTERFERENCE (60) 27,Provisional 2014. application No. 61/931,690, filed on Jan. (71) Applicant: THE BOARD OF TRUSTEE OF Publication Classification THE LELAND STANFORD JUNOR UNIVERSITY, Palo Alto, CA (US) (51) Int. Cl. (72) Inventors: Matthew WHEELER, Sunnyvale, CA CI2N IS/II3 (2006.01) US); Euan A. ASHLEY. Menlo Park (52) U.S. Cl. CA(US), (US); Eua Katheia AA M. , Menlo Park, CPC ......... CI2N 15/113 (2013.01); C12N 2310/14 ZALETA-RIVERA, Stanford, CA (US) (2013.01) (73) Assignee: The Board of Trustees of the Leland (57) ABSTRACT Stanford Junior University, Stanford, Compositions and methods for treating cardiomyopathy CA (US) using RNA interference are disclosed. In particular, embodi ments of the invention relate to the use of oligonucleotides (21) Appl. No.: 15/114,063 for treatment of cardiomyopathy, including Small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) that (22) PCT Filed: Jan. 26, 2015 silence expression of disease-causing mutant alleles, such as the myosin MYL2 allele encoding human regulatory light (86). PCT No.: PCT/US2O15/O12966 chain (hRLC)-N47K and the MYH7 allele encoding human S 371 (c)(1), myosin heavy chain (hMHC)-R403O while retaining (2) Date: Jul. 25, 2016 expression of the corresponding wild-type allele. 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Advantageously, allele-specific targeting allows for direct treatment of underlying disease mechanism in patients 0001. This application is a national stage of Application with inherited cardiomyopathies. Reduction in expression of No. PCT/US2015/012966, filed Jan. 26, 2015, which appli mutated alleles in a site-specific manner promotes normal cation claims priority to U.S. Provisional Application No. allele expression ratio and will facilitate normalization of 61/931,690 filed Jan. 27, 2014, the disclosures of which are protein and myocyte function. Methods and techniques for incorporated herein by reference in their entireties. developing specific cardiac targeting therapeutics are described. Other embodiments of the present invention STATEMENT OF GOVERNMENT SPONSORED include methods for identifying candidate siRNA and SUPPORT shRNA. For example, embodiments of the present invention 0002 This invention was made with Government support include methods and techniques for designing of candidate under contract OD006511 awarded by the National Insti shRNAs that can be advantageously used in certain embodi tutes of Health. The Government has certain rights in this ments of the present invention. invention. 0009 Embodiments of the present invention generally relate to compositions and methods for treating cardiomyo FIELD OF THE INVENTION pathy using RNA interference. Embodiments of the inven 0003. The present invention pertains generally to com tion relate to the use of RNAi oligonucleotides, including positions and methods for treating cardiomyopathy using small interfering RNAs (siRNAs) and short hairpin RNAs RNA interference (RNAi). In particular, the invention (shRNAs), for selective downregulation of human regula relates to the use of oligonucleotides, including Small inter tory light chain (hRLC) and human myosin heavy chain fering RNAs (siRNAs) and short hairpin RNAs (shRNAs) (hMHC) variants for treatment of cardiomyopathy. that preferentially silence expression of mutant alleles of 0010. In an embodiment, two families of silencing con human regulatory light chain (hRLC) and human myosin structs were generated. Another embodiment of the present heavy chain (hMHC) for treatment of cardiomyopathy. invention is a method for identifying and generating a series of vectors capable of treating inherited cardiovascular dis BACKGROUND OF THE INVENTION eases. Exemplary constructs are shown that specifically target mutations responsible for hypertrophic cardiomyopa 0004 Cardiomyopathy is a genetic disease of the heart thy. In an embodiment, silencing constructs of the siRNA muscle and the most common cause of Sudden death in type were generated targeting a single base pair mutation in young people and athletes. It is caused by heterozygotic the MYL2 gene at position 47 of the protein. missense mutations in genes encoding proteins of the car 0011 Mismatch position (e.g., mutant vs. normal allele diac sarcomere. To date, more than 400 mutations in over mismatch) in mature siRNA sequence at position 6, 7, 8 and nine disease genes have been described. 10 are shown to be effective in producing differential silenc 0005 Cardiomyopathy has been linked to a number of ing according to an embodiment of the present invention.
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