IP Library › Granted Patent US 12,480,126
Granted Patent B2
US 12,480,126 · App. 17/814,120 · Granted Nov 25, 2025

Modulation of dystrophia myotonica-protein kinase (DMPK) expression

Inventors: Susan M. Freier (San Diego, CA); Charles A. Thornton (Rochester, NY); Thurman Wheeler (Rochester, NY); Seng H. Cheng (Natick, MA); Andrew Leger (Boston, MA); Bruce M. Wentworth (Northborough, MA)
Assignees: Ionis Pharmaceuticals, Inc.; University of Rochester
C12N15/1137A61P15/00A61P25/18A61P35/00A61P43/00C12N15/113C12Y207/11C12N2310/11C12N2310/315C12N2310/3181C12N2310/321C12N2310/3231C12N2310/3341C12N2310/341C12N2310/346C12N2310/3525
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Quick Facts
Patent No.
US 12,480,126
App. No.
17/814,120
Granted
Nov 25, 2025
Kind
B2
Abstract

Provided herein are methods, compounds, and compositions for reducing expression of a DMPK mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for preferentially reducing CUGexp DMPK RNA, reducing myotonia or reducing spliceopathy in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate type 1 myotonic dystrophy, or a symptom thereof.

Claims (38)

1 . A compound comprising a modified oligonucleotide consisting of 20 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to at least 20 contiguous nucleobases of an equal length portion of nucleobases 2077-2099 of SEQ ID NO:1;

wherein the modified oligonucleotide comprises at least one modified sugar moiety and/or at least one modified internucleoside linkage.

2 . A compound comprising a modified oligonucleotide consisting of 20 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% identical to any of the nucleobase sequences recited in SEQ ID NOs: 590-594, and wherein the modified oligonucleotide comprises at least one modified sugar moiety and/or at least one modified internucleoside linkage.

3 . The compound of claim 1 , wherein the modified oligonucleotide is a single-stranded oligonucleotide.

4 . The compound of claim 1 , wherein the modified oligonucleotide is a double-stranded oligonucleotide.

5 . The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 95% or 100% complementary to at least 20 contiguous nucleobases of an equal length portion of nucleobases 2077-2099 of SEQ ID NO: 1.

6 . The compound of claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage.

7 . The compound of claim 1 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

8 . The compound of claim 1 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

9 . The compound of claim 1 , wherein at least one nucleoside comprises a modified sugar.

10 . The compound of claim 9 , wherein the modified sugar is a bicyclic sugar.

11 . The compound of claim 9 , wherein the modified sugar comprises a 2′-O-methoxyethyl.

12 . The compound of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.

13 . The compound of claim 12 , wherein the modified nucleobase is a 5-methylcytosine.

14 . The compound of claim 1 , wherein the modified oligonucleotide comprises:

a gap segment consisting of 6 to 14 linked deoxynucleosides;

a 5′ wing segment consisting of 3 to 8 linked nucleosides;

a 3′ wing segment consisting of 3 to 8 linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment;

and wherein each nucleoside of each wing segment comprises a modified sugar.

15 . The compound of claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides and comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of five linked nucleosides;

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment;

wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar;

and wherein each internucleoside linkage is a phosphorothioate linkage.

16 . The compound of claim 1 , wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

17 . The compound of claim 1 , further comprising a conjugate group.

18 . The isolated compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to at least 20 contiguous nucleobases of an equal length portion of nucleobases 2079-2099 of SEQ ID NO: 1.

19 . The isolated compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to at least 20 contiguous nucleobases of an equal length portion of nucleobases 2079-2099 of SEQ ID NO: 1.

20 . A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

21 . A method of treating a DMPK related disease or a symptom thereof in an animal in need thereof, wherein the method comprises administering to said animal a therapeutically effective amount of the compound of claim 1 .

22 . The method of claim 21 , wherein the DMPK related disease or a symptom thereof is:

(a) myotonia, or

(b) spliceopathy.

23 . The method of claim 21 , wherein the DMPK related disease or a symptom thereof is type 1 myotonic dystrophy.

24 . The method of claim 21 , wherein the DMPK related disease or a symptom thereof is muscleblind-like protein (MBNL) dependent spliceopathy.