Compositions and methods of treating muscle atrophy and myotonic dystrophy

Patent metadata

Field	Value
Publication number	US-2023201362-A1
Application number	US-202217935922-A
Country	US
Kind code	A1
Filing date	Sep 27, 2022
Priority date	Dec 6, 2017
Publication date	Jun 29, 2023
Grant date	—

Abstract

Disclosed herein are polynucleic acid molecules, pharmaceutical compositions, and methods for treating muscle atrophy or myotonic dystrophy.

First claim

What is claimed is:

1 . A method of treating muscle atrophy or myotonic dystrophy in a subject in need thereof, comprising administering to the subject an siRNA molecule conjugate comprising an anti-transferrin receptor binding moiety conjugated to an siRNA molecule that hybridizes to a target sequence of a human DMPK mRNA and mediates RNA interference against the human DMPK mRNA preferentially in muscle cells in the subject, thereby treating muscle atrophy or myotonic dystrophy in the subject.

2 . The method of claim 1 , wherein the siRNA molecule comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety.

3 . The method of claim 1 , wherein the anti-transferrin receptor binding moiety binds to a transferrin receptor on a cell surface of a muscle cell.

4 . The method of claim 1 , wherein the siRNA molecule comprises the sense strand and an antisense strand, and wherein the sense strand and the antisense strand each independently comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety.

5 . The method of claim 1 , wherein the siRNA molecule hybridizes to at least 8 contiguous bases of the target sequence of the human DMPK mRNA.

6 . The method of claim 1 , wherein the siRNA molecule is from about 8 to about 50 nucleotides in length or from about 10 to about 30 nucleotides in length.

7 . The method of claim 1 , wherein the siRNA molecule conjugate comprises a linker connecting the anti-transferrin receptor binding moiety to the siRNA molecule.

8 . The method of claim 2 , wherein the at least one 2′ modified nucleotide: comprises 2′-O-methyl, 2-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl, 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), or 2′-O-N-methylacetamido (2′-O-NMA) modified nucleotide; comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA); or comprises a combination thereof.

9 . The method of claim 2 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

10 . The method of claim 2 , wherein the siRNA molecule comprises three or more 2′ modified nucleotides selected from 2′-O-methyl modified nucleotide and 2′-deoxy-2′-fluoro modified nucleotide.

11 . The method of claim 1 , wherein the siRNA molecule conjugate has a drug to anti-transferrin receptor binding moiety ratio of from about 1 to about 4.

12 . The method of claim 1 , wherein the siRNA molecule comprises a 5′-terminal vinylphosphonate modified nucleotide.

13 . The method of claim 1 , wherein the muscle atrophy is associated with myotonic dystrophy type 1 (DM1).

14 . The method of claim 1 , wherein the myotonic dystrophy is DM1.

15 . The method of claim 1 , wherein the siRNA molecule conjugate is formulated for parenteral administration.

16 . The method of claim 1 , wherein the target sequence of the human DMPK mRNA comprises exons 1-13 of the human DMPK mRNA excluding CUG repeats.

17 . The method of claim 1 , wherein the anti-transferrin binding moiety is an anti-transferrin receptor antibody or antigen binding fragment thereof.

18 . The method of claim 17 , wherein the anti-transferrin receptor antibody comprises two light chain variable domains and two heavy chain variable domains.

Assignees

• Avidity Biosciences Inc

Inventors

• Geall Andrew John
• Doppalapudi Venkata
• Chu David Sai-Ho
• COCHRAN Michael Caramian
• Hood Michael
• Darimont Beatrice Diana
• Burke Rob
• Shi Yunyu
• Marelius Gulin Erdogan
• Malecova Barbora

Classifications

• A61K9/5107

  Excipients; Inactive ingredients · CPC title

• A61K47/6807 Primary

  the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense · CPC title

• A61K47/6849 Primary

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• C12Y207/11001

  Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase · CPC title

• C12N15/1137

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title