Compound and method for treating myotonic dystrophy

1. An antisense conjugate, or a pharmaceutically acceptable salt thereof, comprising

a phosphorodiamidate morpholino oligomer (PMO) of 8-30 bases comprising a sequence of at least 8 contiguous bases that is complementary to the polyCUG repeats in the 3′-UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in myotonic dystrophy type 1 (DM1), and

a cell-penetrating peptide (CPP) conjugated to the oligomer,

wherein the CPP is conjugated to the antisense oligomer with a linker, and

wherein the CPP and linker together are of a formula selected from the group consisting of:

wherein R a is H or acetyl.

2. The antisense conjugate of claim 1 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

3. The antisense conjugate of claim 1 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

4. The antisense conjugate of claim 1 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

5. The antisense conjugate of claim 1 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

6. The antisense conjugate of claim 1 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

7. The antisense conjugate of claim 1 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

8. The antisense conjugate of claim 1 , or pharmaceutically acceptable salt thereof, wherein the sequence is selected from SEQ ID NOs: 1-14.

9. An antisense conjugate, or a pharmaceutically acceptable salt thereof, comprising

a phosphorodiamidate morpholino oligomer (PMO) of 8-30 bases comprising a sequence of at least 8 contiguous bases that is complementary to the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in myotonic dystrophy type 2 (DM2), and

a cell-penetrating peptide (CPP) conjugated to the oligomer,

wherein the CPP is conjugated to the antisense oligomer with a linker, and

wherein the CPP and linker together are of a formula selected from the group consisting of:

wherein R a is H or acetyl.

10. The antisense conjugate of claim 9 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

11. The antisense conjugate of claim 9 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

12. The antisense conjugate of claim 9 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

13. The antisense conjugate of claim 9 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

14. The antisense conjugate of claim 9 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

15. The antisense conjugate of claim 9 , or pharmaceutically acceptable salt thereof, wherein the CPP and linker together are of the formula:

16. The antisense conjugate of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the sequence is selected from SEQ ID NOs: 19-25.

17. A method of treating myotonic dystrophy type 1 (DM1) or myotonic dystrophy type 2 (DM2) in a mammalian subject in need thereof, comprising administering to the subject an effective amount of an antisense conjugate, or a pharmaceutically acceptable salt thereof, wherein the antisense conjugate or pharmaceutically acceptable salt thereof comprises:

a phosphorodiamidate morpholino oligomer (PMO) of 8-30 bases comprising a sequence of at least 8 contiguous bases that is complementary to the polyCUG repeats in the 3′-UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1, and

a cell-penetrating peptide (CPP) conjugated to the oligomer,

wherein the CPP is conjugated to the antisense oligomer with a linker, and

wherein the CPP and linker together are of a formula selected from the group consisting of:

wherein R a is H or acetyl.

18. The method of claim 17 , wherein the CPP and linker together are of the formula:

19. The method of claim 17 , wherein the CPP and linker together are of the formula:

20. The method of claim 17 , wherein the CPP and linker together are of the formula:

21. The method of claim 17 , wherein the CPP and linker together are of the formula:

22. The method of claim 17 , wherein the CPP and linker together are of the formula:

23. The method of claim 17 , wherein the CPP and linker together are of the formula:

24. The method of claim 17 , wherein the sequence is selected from SEQ ID NOs: 1-14.

25. A method of treating myotonic dystrophy type 2 (DM2) in a mammalian subject in need thereof, comprising administering to the subject an effective amount of an antisense conjugate, or a pharmaceutically acceptable salt thereof, wherein the antisense conjugate or pharmaceutically acceptable salt thereof comprises:

a phosphorodiamidate morpholino oligomer (PMO) of 8-30 bases comprising a sequence of at least 8 contiguous bases that is complementary to the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in DM2, and

a cell-penetrating peptide (CPP) conjugated to the oligomer,

wherein the CPP is conjugated to the antisense oligomer with a linker, and

wherein the CPP and linker together are of a formula selected from the group consisting of:

wherein R a is H or acetyl.

26. The method of claim 25 , wherein the CPP and linker together are of the formula:

27. The method of claim 25 , wherein the CPP and linker together are of the formula:

28. The method of claim 25 , wherein the CPP and linker together are of the formula:

29. The method of claim 25 , wherein the CPP and linker together are of the formula:

30. The method of claim 25 , wherein the CPP and linker together are of the formula:

31. The method of claim 25 , wherein the CPP and linker together are of the formula:

32. The method of claim 25 , wherein the sequence is selected from SEQ ID NOs: 19-25.