# US 10,119,141 B2 · Hippo and dystrophin complex signaling in cardiomyocyte renewal

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- Number: US 10,119,141 B2
- Document ID: US10119141B2
- Status: Granted
- Kind: B2
- Application number: 15/642,200
- Filed: 2017-07-05
- Published: 2017-10-26
- Granted: 2018-11-06
- Earliest claimed: 2013-12-09
- Assignees: Baylor College of Medicine; Texas Heart Institute
- Applicants: Baylor College of Medicine; Texas Heart Institute
- Inventors: James F. Martin; Yuka Morikawa; Todd Ryan Heallen; John Leach
- Web page: https://patentgrep.com/patent/US10119141B2

## CPC

- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 21/04: for myasthenia gravis
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 15/86: Viral vectors
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/531: Stem-loop; Hairpin
- C12N 2320/30: Special therapeutic applications
- C12N 2740/15043: viral genome or elements thereof as genetic vector
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 1

An isolated synthetic nucleic acid composition, comprising SEQ ID NO:10 and/or a derivative nucleic acid comprising at least 80% identity to SEQ ID NO:10, wherein the composition 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.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the derivative nucleic acid is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:10.

### Claim 3 (depends on 1)

The composition of claim 1, wherein said nucleic acid is at least 43 nucleotides in length.

### Claim 4 (depends on 1)

The composition of claim 1, wherein said nucleic acid is no more than 137 nucleotides in length.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the loop structure is between 5 and 19 nucleotides in length.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the derivative nucleic acid has 1, 2, 3, 4, or 5 mismatches compared to SEQ ID NO:10.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the nucleic acid or derivative nucleic acid is comprised in a vector.

### Claim 8 (depends on 7)

The composition of claim 7, wherein the vector is a viral vector.

### Claim 9 (depends on 7)

The composition of claim 7, wherein the vector is a non-viral vector.

### Claim 10 (depends on 7)

The composition of claim 7, wherein the vector is a non-integrating vector.

### Claim 11 (depends on 10)

The composition of claim 10, wherein the non-integrating vector is a lentiviral vector.

### Claim 12 (depends on 7)

The composition of claim 7, wherein the expression of the nucleic acid is regulated by a tissue-specific or cell-specific promoter.

### Claim 13 (depends on 12)

The composition of claim 12, wherein the promoter is a cardiomyocyte-specific promoter.

### Claim 14 (depends on 13)

The composition of claim 13, 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.

### Claim 15 (depends on 7)

The composition of claim 7, wherein a same vector comprises SEQ ID NO:10 and 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:11, or SEQ ID NO:12.

### Claim 16 (depends on 15)

The composition of claim 15, wherein the two or more nucleic acids are regulated by the same regulatory sequence.

### Claim 17 (depends on 15)

The composition of claim 15, wherein the two or more nucleic acids are regulated by a different regulatory sequence.