# US 9,752,143 B2 · Locked nucleic acid inhibitor of miR-145 and uses thereof

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- Number: US 9,752,143 B2
- Document ID: US9752143B2
- Status: Granted
- Kind: B2
- Application number: 14/777,172
- Filed: 2014-03-13
- Published: 2016-01-14
- Granted: 2017-09-05
- Earliest claimed: 2013-03-15
- Assignees: Miragen Therapeutics, Inc.
- Applicants: Miragen Therapeutics, Inc.
- Inventors: Anita G. Seto; Eva van Rooij; Kathryn H. Hutnick; Christina M. Dalby; Thomas G. Hullinger; Rusty Montgomery
- Web page: https://patentgrep.com/patent/US9752143B2

## 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 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C12N 2310/113: targeting other non-coding nucleic acids, e.g. antagomirs
- 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: 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The present invention provides oligonucleotides with chemical motifs that are miR-145 inhibitors. The oligonucleotides can be used for the treatment and prevention of a condition by inhibiting the expression or activity of miR-145 in cells of a subject in need thereof. Methods provided include treating or preventing pulmonary arterial hypertension, neointima formation, restenosis or hypertension in a subject in need thereof by administering to the subject an inhibitor of miR-145 expression or activity. Pharmaceutical compositions and kits comprising miR-145 inhibitors are also disclosed.

## Claims

### Claim 1

An oligonucleotide comprising a sequence complementary to the seed region of miR-145, wherein the seed region is 5′-UCCAGUUU-3′ (SEQ ID NO: 7), wherein the oligonucleotide consists of sixteen nucleotides, wherein from the 5′ end to the 3′ end, the oligonucleotide comprises LNAs at positions 1, 6, 11, 13 and 15 of the sequence, and wherein the oligonucleotide comprises at least one non-locked nucleotide.

### Claim 2 (depends on 1)

The oligonucleotide of claim 1, wherein the oligonucleotide comprises a LNA at a 5′ end, a 3′ end or both a 5′ and a 3′ end.

### Claim 3 (depends on 1)

The oligonucleotide of claim 1, wherein the oligonucleotide comprises no more than three contiguous LNAs.

### Claim 4 (depends on 1)

The oligonucleotide of claim 1, wherein the oligonucleotide comprises at least nine LNAs.

### Claim 5 (depends on 4)

The oligonucleotide of claim 4, wherein from the 5′end to the 3′ end of the oligonucleotide, positions 5, 9, 10 and 16 are LNAs.

### Claim 6 (depends on 4)

The oligonucleotide of claim 4, wherein from the 5′end to the 3′ end of the oligonucleotide, positions 2, 8, 10 and 16 are LNAs.

### Claim 7 (depends on 1)

The oligonucleotide of claim 1, wherein at least one of the non-locked nucleotides is 2′ deoxy, 2′ O-alkyl or 2′ halo.

### Claim 8 (depends on 1)

The oligonucleotide of claim 1, wherein the oligonucleotide has a 5′ cap structure, 3′ cap structure, or 5′ and 3′ cap structure.

### Claim 9 (depends on 1)

The oligonucleotide of claim 1, wherein the oligonucleotide comprises one or more phosphorothioate linkages.

### Claim 10 (depends on 1)

The oligonucleotide of claim 1, wherein the oligonucleotide has one to three phosphate linkages.

### Claim 11 (depends on 1)

The oligonucleotide of claim 1, further comprising a pendant lipophilic group.

### Claim 12 (depends on 1)

The oligonucleotide of claim 1, wherein the oligonucleotide increases the expression of a miR-145 target gene in a cell relative to a saline control, and the increase in expression has a p-value of <0.05.

### Claim 13 (depends on 12)

The oligonucleotide of claim 12, wherein the miR-145 target gene is Klf4, Klf5, Lrrc71, Nedd41, Igf1r, Sec1412, Megf6, Fmod, Ankrd12, Golga1, Gpbp1, Hist3h2a, Rapgef2, or Sned1.

### Claim 14 (depends on 1)

A method of reducing or inhibiting activity of miR-145 in a cell comprising contacting the cell with the oligonucleotide of claim 1.

### Claim 15 (depends on 1)

A method of inhibiting smooth muscle cell proliferation comprising contacting a smooth muscle cell with the oligonucleotide of claim 1.

### Claim 16 (depends on 1)

A method of inhibiting or treating restenosis or neointima formation in a subject comprising administering to the subject a pharmaceutical composition comprising the oligonucleotide of claim 1.

### Claim 17 (depends on 1)

A method of treating or preventing hypertension in a subject comprising administering to the subject a pharmaceutical composition comprising the oligonucleotide of claim 1.

### Claim 18 (depends on 1)

The oligonucleotide of claim 1, wherein the oligonucleotide has increased in vivo efficacy as compared to a second oligonucleotide comprising the same sequence and LNA composition and different LNA motif.

### Claim 19 (depends on 18)

The oligonucleotide of claim 18, wherein the oligonucleotide has increased lung efficacy as compared to the second oligonucleotide.