# US 9,752,144 B2 · Inhibitors of MYH7B and uses thereof

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- Number: US 9,752,144 B2
- Document ID: US9752144B2
- Status: Granted
- Kind: B2
- Application number: 14/818,144
- Filed: 2015-08-04
- Published: 2016-02-04
- Granted: 2017-09-05
- Earliest claimed: 2014-08-04
- Assignees: Miragen Therapeutics, Inc.
- Applicants: MiRagen Therapeutics, Inc.
- Inventors: Rusty Montgomery; Christina Dalby
- Web page: https://patentgrep.com/patent/US9752144B2

## 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 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/346: having a combination of backbone and sugar modifications
- 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

The present invention provides nucleic acid inhibitors of MYH7B and compositions thereof. The present invention also provides methods of treating or preventing a cardiac disorder such as cardiac hypertrophy, myocardial infarction, or heart failure in a subject by administering to the subject an inhibitor of MYH7B. The present invention further provides methods of modulating the activity or expression of β-MHC in cardiac cells of a subject by administering to the subject an inhibitor of MYH7B.

## Claims

### Claim 1

An antisense oligonucleotide inhibitor of MYH7B containing at least one modified nucleotide, wherein the antisense oligonucleotide is 8 to 18 nucleotides and wherein the sequence of the antisense oligonucleotide is completely complementary to a sequence of SEQ ID NO: 6 from nucleotides 4300-4317, nucleotides 4302-4315, or nucleotides 4318-4331.

### Claim 2 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein the antisense oligonucleotide is 14 nucleotides and the sequence of the antisense oligonucleotide is completely complementary to a sequence of SEQ ID NO: 6 from nucleotides 4300-4317.

### Claim 3 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein the antisense oligonucleotide is 14 nucleotides and the sequence of the antisense oligonucleotide is completely complementary to the sequence of SEQ ID NO: 6 from nucleotides 4302-4315.

### Claim 4 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein the antisense oligonucleotide is 14 nucleotides and the sequence of the antisense oligonucleotide is completely complementary to the sequence of SEQ ID NO: 6 from nucleotides 4318-4331.

### Claim 5 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein said modified nucleotide includes a sugar, base, or a backbone modification.

### Claim 6 (depends on 5)

The antisense oligonucleotide inhibitor of claim 5, wherein the sugar modification is selected from the group consisting of 2′-O, 4′-C methylene bridge, 2′-O, 4′-C ethylene bridge, 2′-CH2—NH—CH2-4′ bridge, 2′-deoxy, 2′-O-alkyl, and 2′-halo modifications.

### Claim 7 (depends on 5)

The antisense oligonucleotide inhibitor of claim 5, wherein the backbone modification is a phosphorothioate linkage.

### Claim 8 (depends on 7)

The antisense oligonucleotide inhibitor of claim 7, wherein said antisense oligonucleotide contains two or more phosphorothioate linkages.

### Claim 9 (depends on 8)

The antisense oligonucleotide inhibitor of claim 8, wherein said antisense oligonucleotide is fully phosphorothioate linked.

### Claim 10 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein said modified nucleotide is a locked nucleotide.

### Claim 11 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein said antisense oligonucleotide contains one to six locked nucleotides.

### Claim 12 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein said antisense oligonucleotide contains at least three locked nucleotides at the 5′ end.

### Claim 13 (depends on 12)

The antisense oligonucleotide inhibitor of claim 12, wherein the at least three locked nucleotides at the 5′ end are ribonucleotides.

### Claim 14 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein said antisense oligonucleotide contains at least three locked nucleotides at the 3′ end.

### Claim 15 (depends on 14)

The antisense oligonucleotide inhibitor of claim 14, wherein the at least three locked nucleotides at the 3′ end are ribonucleotides.

### Claim 16 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein said antisense oligonucleotide contains at least one deoxyribonucleotide.

### Claim 17 (depends on 16)

The antisense oligonucleotide inhibitor of claim 16, wherein said antisense oligonucleotide contains two to eight deoxyribonucleotides.

### Claim 18 (depends on 1)

The antisense oligonucleotide inhibitor of claim 1, wherein said modified nucleotide is 5′-methyl cytidine.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising the antisense oligonucleotide inhibitor of MYH7B of claim 1 and a pharmaceutically acceptable excipient.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19, further comprising a second therapeutic agent, wherein the second therapeutic agent is an antisense oligonucleotide inhibitor of miR-208a, miR-208b, miR-499, miR-15a, miR-15b, miR-16, miR-195, or a mixture thereof.

### Claim 21

An antisense oligonucleotide inhibitor of MYH7B containing at least one modified nucleotide, and wherein said antisense oligonucleotide comprises a sequence selected from Tables 1-5.

### Claim 22 (depends on 21)

The antisense oligonucleotide inhibitor of claim 21, wherein said antisense oligonucleotide comprises the sequence of 5′-lTslTslGsdAsdTsdCsdTsdTsdGsdGsdCslCslTslC-3′ (SEQ ID NO: 146) or 5′ -lCslTslGsdCsdAsdGsdCsdTsdCsdCsdTslCslCslA-3′ (SEQ ID NO: 148).

### Claim 23 (depends on 21)

The antisense oligonucleotide inhibitor of claim 21, wherein said antisense oligonucleotide comprises the sequence of 5′-lCslCslAsdGsdGsdAsdGsmdCsmdCsdTsdAslTslTslC-3′ (SEQ ID NO: 494).

### Claim 24 (depends on 21)

The antisense oligonucleotide inhibitor of claim 21, wherein said antisense oligonucleotide comprises the sequence of 5′-lGslTslTsmdCsdAsmdCsdTsmdCsdAsmdCsdAslTslCslC-3′ (SEQ ID NO: 188).

### Claim 25 (depends on 21)

The antisense oligonucleotide inhibitor of claim 21, wherein said antisense oligonucleotide comprises the sequence of 5′-lAslGslTsdTsmdCsdAsmdCsdTsmdCsdAsmdCslAslTslC-3′ (SEQ ID NO: 190).

### Claim 26 (depends on 21)

The antisense oligonucleotide inhibitor of claim 21, wherein said antisense oligonucleotide comprises the sequence of 5′-lAslGslTsdTsdAsdTsmdCsdAsdTsdTsmdCslCslTslC-3′ (SEQ ID NO: 370).

### Claim 27 (depends on 21)

The antisense oligonucleotide inhibitor of claim 21, wherein said antisense oligonucleotide comprises the sequence of 5′-lCslTslTsdAsdGsmdCsdTsdGsdAsdTsmdCslCslTslC-3′ (SEQ ID NO: 568).

### Claim 28 (depends on 21)

A pharmaceutical composition comprising the antisense oligonucleotide inhibitor of MYH7B of claim 21 and a pharmaceutically acceptable excipient.

### Claim 29 (depends on 28)

The pharmaceutical composition of claim 28, further comprising a second therapeutic agent, wherein the second therapeutic agent is an antisense oligonucleotide inhibitor of miR-208a, miR-208b, miR-499, miR-15a, miR-15b, miR-16, miR-195, or a mixture thereof.