Compositions and methods of treating muscle atrophy and myotonic dystrophy

Patent metadata

Field	Value
Publication number	US-2023047754-A1
Application number	US-202217822342-A
Country	US
Kind code	A1
Filing date	Aug 25, 2022
Priority date	Dec 6, 2017
Publication date	Feb 16, 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 small interfering RNA (siRNA) conjugate comprising a binding moiety conjugated to a siRNA that hybridizes to a target sequence in exons 1 - 13 of human DMPK mRNA excluding CUG repeats and mediates RNA interference against the human DMPK mRNA preferentially in a muscle cell in a subject, wherein the siRNA is a double stranded RNA comprising a guide strand and a passenger strand.

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

3 . The siRNA conjugate of claim 1 , wherein mediation of RNA interference against the human DMPK mRNA modulates muscle atrophy or myotonic dystrophy in said subject.

4 . The siRNA conjugate of claim 1 , wherein the binding moiety binds to a receptor on the cell surface of the muscle cell.

5 . The siRNA conjugate of claim 1 , wherein the guide strand and the passenger strand are 8 to 30 nucleotides in length.

6 . The siRNA conjugate of claim 1 , wherein the siRNA hybridizes to at least 8 contiguous nucleotides of the target sequence in the exons 1 - 13 of the human DMPK mRNA.

7 . The siRNA conjugate of claim 1 , wherein the siRNA conjugate comprises a linker connecting the binding moiety to the siRNA.

8 . The siRNA conjugate 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 siRNA conjugate of claim 2 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

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

11 . The siRNA conjugate of claim 1 , wherein the siRNA conjugate has a drug to binding moiety ratio of from about 1 to about 4.

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

13 . The siRNA conjugate of claim 1 , wherein the binding moiety is a polypeptide or a peptide.

14 . The siRNA conjugate of claim 13 , wherein the polypeptide or the peptide is selected from a plasma protein and a bicyclic peptide.

15 . The siRNA conjugate of claim 1 , wherein the binding moiety is a steroid, a polymer, a small molecule, or a polynucleic acid that does not hybridize to a target gene or mRNA.

16 . The siRNA conjugate of claim 3 , wherein the muscle atrophy is associated with myotonic dystrophy type 1 (DM1).

17 . The siRNA conjugate of claim 3 , wherein the myotonic dystrophy is DM1.

18 . The siRNA conjugate of claim 1 , wherein the siRNA conjugate is formulated for parenteral administration.

19 . The siRNA conjugate of claim 1 , wherein the guide strand is selected from a group consisting of SEQ ID NOs: 6111-8814 and 11519-14222.

20 . The siRNA conjugate of claim 1 , wherein the passenger strand is selected from a group consisting of SEQ ID NOs: 3407-6110 and 8815-11518.

21 . The siRNA conjugate of claim 1 , wherein the guide strand that hybridizes to a target sequence in exons 2 - 13 of the human DMPK mRNA is selected from SEQ ID NOs: 11903, 11961, 11962, 11963, 12051, 12052, 12053, 12057, 12058, 12059, 12061, 12062, 12094, 12095, 12099, 12101, 12102, 12208, 12234, 12235, 12303, 12304, 12307, 12544, 12545, 12546, 12547, 12555, 12557, 12559, 12561, 12562, 12565, 12589, 12591, 12780, 12781, 12782, 12783, 12785, 12786, 12787, 12792, 12794, 12801, 12815, 12860, 12861, 12862, 12864, 13343, 13404, 13408, 13416, 13463, 13478, 13644, 13645, 13667, 13668, 13786, 13790, 14046, 14047, 14048, 14049, 14050, 14072, 14076, 14118, 14146, 14147, 14149, 14154, 14157, 14193, 14194, 14197, 14198, 14199, and 14200.

22 . The siRNA conjugate of claim 1 , wherein the passenger strand that hybridizes to a target sequence in exons 2 - 13 of the human DMPK mRNA is selected from SEQ ID NOs: 9199, 9257, 9258, 9259, 9347, 9348, 9349, 9353, 9354, 9355, 9357, 9358, 9390, 9391, 9395, 9397, 9398, 9504, 9530, 9531, 9599, 9600, 9603, 9840, 9841, 9842, 9843, 9851, 9853, 9855, 9857, 9858, 9861, 9885, 9887, 10076, 10077, 10078, 10079, 10081, 10082, 10083, 10088, 10090, 10097, 10111, 10156, 10157, 10158, 10160, 10639, 10700, 10704, 10712, 10759, 10774, 10940, 10941, 10963, 10964, 11082, 11086, 11342, 11343, 11344, 11345, 11346, 11368, 11372, 11414, 11442, 11443, 11445, 11450, 11453, 11489, 11490, 11493, 11494, 11495, and 11496.

23 . The siRNA conjugate of claim 21 , wherein the guide strand that hybridizes to a target sequence in exons 4 , 5 , and 6 of the human DMPK mRNA is selected from SEQ ID NOs: 12102, 12234, 12303, 12304, and 12307.

24 . The siRNA conjugate of claim 22 , wherein the passenger strand that hybridizes to a target sequence in exons 4 , 5 , and 6 of the human DMPK mRNA is selected from SEQ ID NOs: 9398, 9530, 9599, 9600, and 9603.

25 . The siRNA conjugate of claim 21 , wherein the guide strand that hybridizes to a target sequence in exons 7 and 8 of the human DMPK mRNA is selected from SEQ ID NOs: 12544, 12545, 12546, 12547, 12555, 12557, 12559, 12561, 12562, 12565, 12589, 12783 and 12815.

26 . The siRNA conjugate of claim 22 , wherein the passenger strand of the siRNA that hybridizes to a target sequence in exons 7 and 8 of the human DMPK mRNA is selected from SEQ ID NOs: 9840, 9841, 9842, 9843, 9851, 9853, 9855, 9857, 9858, 9861, 9885, 10079 and 10111.

27 . The siRNA conjugate of claim 21 , wherein the guide strand of the siRNA that hybridizes to a target sequence in exon 9 of the human DMPK mRNA is selected from SEQ ID NOs: 12860, 12861, 12862, and 12864.

28 . The siRNA conjugate of claim 22 , wherein the passenger strand that hybridizes to a target sequence in exon 9 of the human DMPK mRNA is selected from SEQ ID NOs: 10156, 10157, 10158, and 10160.

29 . The siRNA conjugate of claim 21 , wherein the guide strand that hybridizes to a target sequence in exon 13 of the human DMPK mRNA is selected from SEQ ID NOs: 13343, 13463, 13478, 14047, 14048, 14049, 14072, 14146, 14147, 14199, and 14200.

30 . The siRNA conjugate of claim 22 , wherein the passenger strand that hybridizes to a target sequence in exon 13 of the human DMPK mRNA is selected from SEQ ID NOs: 10639, 10759, 10774, 11343, 11344, 11345, 11368, 11442, 11443, 11495, and 11496.

31 . A method of treating myotonic dystrophy in a subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of a small interfering RNA (siRNA) conjugate comprising a binding moiety conjugated to a siRNA that hybridizes to a target sequence in exons 1 - 13 of human DMPK mRNA excluding CUG repeats, wherein the siRNA is 8 to 30 nucleotides in length, thereby treating myotonic dystrophy in said subject.

32 . The method of claim 31 , wherein the myotonic dyst

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