# US 10,246,714 B2 · RNA interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (CTNNB1) gene expression using short interfering nucleic acid (siNA)

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- Number: US 10,246,714 B2
- Document ID: US10246714B2
- Status: Granted
- Kind: B2
- Application number: 15/671,220
- Filed: 2017-08-08
- Published: 2018-02-01
- Granted: 2019-04-02
- Earliest claimed: 2010-08-02
- Assignees: Sirna Therapeutics, Inc.
- Applicants: Sirna Therapeutics, Inc.
- Inventors: Duncan Brown; James J. Cunningham; Marian Gindy; Victoria Pickering; Matthew G. Stanton; Steven M. Stirdivant; Walter R. Strapps
- Web page: https://patentgrep.com/patent/US10246714B2

## CPC

- C12N 15/1138: {against receptors or cell surface proteins}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/332: Abasic residue
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/3521: Methyl
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of CTNNB1 gene expression and/or activity, and/or modulate a beta-catenin gene expression pathway. Specifically, the invention relates to double-stranded nucleic acid molecules including small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules that are capable of mediating or that mediate RNA interference (RNAi) against CTNNB1 gene expression.

## Claims

### Claim 1

A method of treating a human subject suffering from a condition which is mediated by the action of cadherin-associated protein, beta 1 (CTNNB1), comprising administering to said subject an effective amount of a double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of CTNNB1, wherein
(a) the siNA comprises a sense strand and an antisense strand;
(b) each strand is independently 15 to 30 nucleotides in length; and
(c) the sense strand comprises at least 15 nucleotides of the nucleotide sequence of SEQ ID NO: 5, thereby treating the human subject suffering from a condition which is mediated by the action of CTNNB1.

### Claim 2 (depends on 1)

The method of claim 1, wherein the condition is cancer.

### Claim 3 (depends on 1)

The method of claim 1, wherein the double-stranded short interfering nucleic acid (siNA) molecule is administered in a pharmaceutically acceptable carrier or diluent.

### Claim 4 (depends on 3)

The method of claim 3, wherein the pharmaceutically acceptable carrier or diluent comprises
(a) (13Z, 16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
(b) cholesterol;
(c) DSPC; and
(d) PEG-DMG.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antisense strand comprises at least 15 nucleotides having sequence complementarity to 5′-CUGUUGGAUUGAUUCGAAA-3′ (SEQ ID NO:5).

### Claim 6 (depends on 1)

The method of claim 1, wherein the antisense strand comprises at least a 15 nucleotide sequence of 5′-UUUCGAAUCAAUCCAACAG-3′ (SEQ ID NO:4918).

### Claim 7 (depends on 1)

The method of claim 1, wherein the sense strand of the siNA molecule comprises the nucleotide sequence 5′-B CUgUUggaUUgaUUCgaauu B-3′ (SEQ ID NO:6370) and the antisense strand of the siNA molecule comprises the nucleotide sequence 5′-uuucGAauCaAUCcAaCaGUU-3′ (SEQ ID NO:6369),
wherein A, C, G, and U are ribose A, C, G, and U; a, c, g, and u are 2′-deoxy-2′-fluoro A, C, G, and U; A, C, G, and U are 2′-O-methyl A, C, G, and U; and B is an inverted abasic nucleotide.

### Claim 8 (depends on 1)

The method of claim 1, wherein the sense strand of the siNA molecule comprises the nucleotide sequence 5′-B CUGUUGGAUUGAUUCGAAAUsUsB-3′(SEQ ID NO:2021) and the antisense strand of the siNA molecule comprises the nucleotide sequence 5′-uuucGAauCaAUCcAaCaGUsU-3′ (SEQ ID NO:2068);
wherein A, C, G, and U are ribose A, C, G, and U; a, c, g, and u are 2′-deoxy-2′-fluoro A, C, G, and U; A, C, G, and U are 2′-O-methyl A, C, G, and U; s is a phosphorothioate linkage; and B is an inverted abasic nucleotide.

### Claim 9 (depends on 1)

The method of claim 1, wherein at least one nucleotide of the double-stranded short interfering nucleic acid (siNA) molecule is a chemically modified nucleotide.

### Claim 10 (depends on 9)

The method of claim 9, wherein the chemically modified nucleotide is a 2′-deoxy-2′-fluoro nucleotide.

### Claim 11 (depends on 9)

The method of claim 9, wherein the chemically modified nucleotide is a 2′-deoxy nucleotide.

### Claim 12 (depends on 9)

The method of claim 9, wherein the chemically modified nucleotide is a 2′-O-alkyl nucleotide.

### Claim 13 (depends on 1)

The method of claim 1, wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises at least one non-nucleotide.

### Claim 14 (depends on 1)

The method of claim 1, wherein at least one nucleotide of the double-stranded short interfering nucleic acid (siNA) molecule comprises a universal base.

### Claim 15 (depends on 1)

The method of claim 1, wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises at least one phosphorothioate internucleotide linkage.

### Claim 16 (depends on 1)

The method of claim 1, wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises a cap on the 3′-end of at least one strand.

### Claim 17 (depends on 1)

The method of claim 1, wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises a cap on the 5′-end of at least one strand.

### Claim 18 (depends on 1)

The method of claim 1, wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises a cap on both 3′- and 5′-ends of at least one strand.

### Claim 19 (depends on 1)

The method of claim 1, wherein the double-stranded short interfering nucleic acid (siNA) molecule comprises one or more 3′-overhang nucleotides on one or both strands.

### Claim 20 (depends on 19)

The method of claim 19, wherein the 3′-overhang nucleotides on at least one strand of the double-stranded short interfering nucleic acid (siNA) molecule are 2′-O-methyl nucleotides.

### Claim 21 (depends on 20)

The method of claim 20, wherein the 2′-O-methyl nucleotides on at least one strand of the double-stranded short interfering nucleic acid (siNA) molecule are linked with a phosphorothioate internucleotide linkage.

### Claim 22 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 23 (depends on 1)

The method of claim 1, wherein the double stranded siNA is administered to the subject intravenously, subcutaneously or intramuscularly.