US2019040388A1PendingUtilityA1

Hippo and dystrophin complex signaling in cardiomyocyte renewal

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Assignee: BAYLOR COLLEGE MEDICINEPriority: Dec 9, 2013Filed: Oct 18, 2018Published: Feb 7, 2019
Est. expiryDec 9, 2033(~7.4 yrs left)· nominal 20-yr term from priority
Inventors:James F. MartinYuka MorikawaTodd Ryan HeallenJohn Leach
A61P 9/00A61P 9/04A61P 9/10A61P 21/04C12N 2310/531A61K 31/713C12N 2320/30C12N 7/00C12N 2310/14C12N 15/86C12N 15/113C12N 2740/15043C12N 2750/14143
65
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Claims

Abstract

Embodiments of the disclosure include methods and compositions for the renewal of cardiomyocytes by targeting the Hippo pathway. In particular embodiments, an individual with a need for cardiomyocyte renewal is provided an effective amount of a shRNA molecule that targets the Sav1 gene. Particular shRNA sequences are disclosed.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . An isolated synthetic nucleic acid composition, comprising SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12 and/or a derivative nucleic acid comprising at least 80% identity to one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12. 
     
     
         2 . The composition of  claim 1 , wherein the derivative nucleic acid is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12. 
     
     
         3 . The composition of  claim 1 , wherein the nucleic acid comprises the sequence of SEQ ID NO:4 and further comprises an antisense sequence of SEQ ID NO:4, wherein when the sequence and the antisense sequence are hybridized together to form a duplex structure, the sequence and the antisense sequence are separated by a loop structure. 
     
     
         4 . The composition of  claim 1 , wherein the nucleic acid comprises the sequence of SEQ ID NO:5 and further comprises an antisense sequence of SEQ ID NO:5, wherein when the sequence and the antisense sequence are hybridized together to form a duplex structure, the sequence and the antisense sequence are separated by a loop structure. 
     
     
         5 . The composition of  claim 1 , wherein the nucleic acid comprises the sequence of SEQ ID NO:6 and further comprises an antisense sequence of SEQ ID NO:6, wherein when the sequence and the antisense sequence are hybridized together to form a duplex structure, the sequence and the antisense sequence are separated by a loop structure. 
     
     
         6 . The composition of  claim 1 , wherein the nucleic acid comprises the sequence of SEQ ID NO:7 and further comprises an antisense sequence of SEQ ID NO:7, wherein when the sequence and the antisense sequence are hybridized together to form a duplex structure, the sequence and the antisense sequence are separated by a loop structure. 
     
     
         7 . The composition of  claim 1 , wherein the nucleic acid comprises the sequence of SEQ ID NO:8 and further comprises an antisense sequence of SEQ ID NO:8, wherein when the sequence and the antisense sequence are hybridized together to form a duplex structure, the sequence and the antisense sequence are separated by a loop structure. 
     
     
         8 . The composition of  claim 1 , wherein the nucleic acid comprises the sequence of SEQ ID NO:9 and further comprises an antisense sequence of SEQ ID NO:9, wherein when the sequence and the antisense sequence are hybridized together to form a duplex structure, the sequence and the antisense sequence are separated by a loop structure. 
     
     
         9 . The composition of  claim 1 , wherein the nucleic acid comprises the sequence of SEQ ID NO:10 and further comprises an antisense sequence of SEQ ID NO:10, wherein when the sequence and the antisense sequence are hybridized together to form a duplex structure, the sequence and the antisense sequence are separated by a loop structure. 
     
     
         10 . The composition of  claim 1 , wherein the nucleic acid comprises the sequence of SEQ ID NO:11 and further comprises an antisense sequence of SEQ ID NO:11, wherein when the sequence and the antisense sequence are hybridized together to form a duplex structure, the sequence and the antisense sequence are separated by a loop structure. 
     
     
         11 . The composition of  claim 1 , wherein the nucleic acid comprises the sequence of SEQ ID NO:12 and further comprises an antisense sequence of SEQ ID NO:12, wherein when the sequence and the antisense sequence are hybridized together to form a duplex structure, the sequence and the antisense sequence are separated by a loop structure. 
     
     
         12 . The composition of  claim 3 , wherein said nucleic acid is at least 43 nucleotides in length. 
     
     
         13 . The composition of  claim 3 , wherein said nucleic acid is no more than 137 nucleotides in length. 
     
     
         14 . The composition of  claim 3 , wherein the loop structure is between 5 and 19 nucleotides in length. 
     
     
         15 . The composition of  claim 1 , wherein the derivative nucleic acid has 1, 2, 3, 4, or 5 mismatches compared to the respective SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12. 
     
     
         16 . The composition of  claim 1 , wherein the nucleic acid or derivative nucleic acid is comprised in a vector. 
     
     
         17 . The composition of  claim 16 , wherein the vector is a viral vector. 
     
     
         18 . The composition of  claim 16 , wherein the vector is a non-viral vector. 
     
     
         19 . The composition of  claim 16 , wherein the vector is a non-integrating vector. 
     
     
         20 . The composition of  claim 19 , wherein the non-integrating vector is a lentiviral vector. 
     
     
         21 . The composition of  claim 16 , wherein the expression of the nucleic acid is regulated by a tissue-specific or cell-specific promoter. 
     
     
         22 . The composition of  claim 21 , wherein the promoter is a cardiomyocyte-specific promoter. 
     
     
         23 . The composition of  claim 22 , wherein the cardiomyocyte-specific promoter is rat ventricle-specific cardiac myosin light chain 2 (MLC-2v) promoter; cardiac muscle-specific alpha myosin heavy chain (MHC) gene promoter; cardiac cell-specific minimum promoter from -137 to +85 of NCX1 promoter; chicken cardiac troponin T (cTNT), or a combination thereof. 
     
     
         24 . The composition of  claim 16 , wherein two or more of nucleic acids comprising SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12 are present on the same vector. 
     
     
         25 . The composition of  claim 24 , wherein the two or more nucleic acids are regulated by the same regulatory sequence. 
     
     
         26 . The composition of  claim 24 , wherein the two or more nucleic acids are regulated by a different regulatory sequence. 
     
     
         27 . A method of treating an individual for a cardiac condition, comprising the step of providing an effective amount of a composition of  claim 1  to the individual. 
     
     
         28 . The method of  claim 27 , wherein the cardiac condition in the individual causes the individual to be in need of cardiomyocyte renewal. 
     
     
         29 . The method of  claim 27 , wherein the heart of the individual has cardiomyocyte apoptosis, necrosis, and/or autophagy. 
     
     
         30 . The method of  claim 27 , wherein the cardiac condition comprises cardiovascular disease, cardiomyopathy, heart failure, myocardial infarction, ischemia, necrosis, fibrosis, or diabetic cardiomyopathy, age-related cardiomyopathy. 
     
     
         31 . The method of  claim 27 , wherein the individual has Duchenne muscular dystrophy. 
     
     
         32 . The method of  claim 27 , wherein the composition is provided to the individual more than once. 
     
     
         33 . The method of  claim 27 , wherein the composition is provided to the individual systemically. 
     
     
         34 . The method of  claim 27 , wherein the composition is provided to the individual locally. 
     
     
         35 . The method of  claim 27 , wherein the individual is provided an additional therapy for the cardiac condition. 
     
     
         36 . A kit comprising a composition of  claim 1 , wherein the composition is housed in a suitable container. 
     
     
         37 . A method of treating a cardiac condition in an individual, comprising the step of providing to the individual a therapeutically effective amount of a shRNA that targets Salvador (Sav1). 
     
     
         38 . The method of  claim 37 , wherein the shRNA is provided to the individual in the AAV9 vector. 
     
     
         39 . The method of  claim 37 , wherein the individual has Duchenne muscular dystrophy.

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