Compound and method for treating myotonic dystrophy

1. An antisense compound, comprising

an uncharged antisense oligomer of 8-30 bases comprising a sequence of at least 8 contiguous bases that is complementary to: (i) the polyCUG repeats in the 3′-UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in Myotonic dystrophy type 1 (DM1) or (ii) 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 of a formula selected from the group consisting of:

wherein independently for each instance R a is H or acetyl.

2. The antisense compound of claim 1 , wherein the CPP is conjugated to the antisense oligomer with a linker selected from glycine (G), cysteine (C), 6-aminohexanoic acid (Ahx), β-alanine (B), and AhxB.

3. The antisense compound of claim 2 , wherein the linker is G.

4. The antisense compound of claim 2 , wherein the CPP and linker together are of a formula selected from the group consisting of:

wherein independently for each instance R a is H or acetyl.

5. The antisense compound of claim 1 , wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer (PMO) having a sequence complementary to the polyCUG repeats in the 3′-UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1.

6. The antisense compound of claim 5 , wherein the sequence is selected from SEQ ID NOs: 1-14.

7. The antisense compound of claim 1 , wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer (PMO) having a sequence complementary to the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in DM2.

8. The antisense compound of claim 7 , wherein the sequence is selected from SEQ ID NOs: 19-25.

9. An antisense compound, comprising:

an antisense oligomer of 8-30 morpholino subunits linked together by phosphorodiamidate linkages, wherein:

each morpholino subunit is of a formula:

wherein each B is a base pairing moiety independently selected from adenine, cytosine, guanine, uracil, thymine or hypoxanthine, wherein each B taken together comprises a sequence of at least 8 contiguous bases that is complementary to: (i) the polyCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in Myotonic dystrophy type 1 (DM1) or (ii) the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in Myotonic dystrophy type 2 (DM2); and

each phosphorodiamidate linkage is of a formula:

 and

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

the CPP is of a formula selected from the group consisting of:

wherein independently for each instance R a is H or acetyl, and the CPP is conjugated to the morpholino oligomer by a linker selected from:

10. The antisense compound of claim 9 , wherein the CPP and linker together are of a formula selected from the group consisting of:

wherein independently for each instance R a is H or acetyl.

11. The antisense compound of claim 9 , wherein the sequence is complementary to the polyCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1.

12. The antisense compound of claim 11 , wherein the sequence is selected from SEQ ID NOs: 1-14.

13. The antisense compound of claim 9 , wherein the sequence is complementary to the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in DM2.

14. The antisense compound of claim 13 , wherein the sequence is selected from SEQ ID NOs: 19-25.

15. 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 compound, wherein the antisense compound comprises:

an antisense oligomer of 8-30 morpholino subunits linked together by phosophorodiamidate linkages, wherein:

each morpholino subunit is of a formula:

wherein each B is a base pairing moiety independently selected from adenine, cytosine, guanine, uracil, thymine or hypoxanthine, wherein each B taken together comprises a sequence of at least 8 contiguous bases that is complementary to: (i) the polyCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in Myotonic dystrophy type 1 (DM1) or (ii) the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in Myotonic dystrophy type 2 (DM2); and

each phosphorodiamidate linkage is of a formula:

 and

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

the CPP is of a formula selected from the group consisting of:

wherein independently for each instance R a is H or acetyl, and the CPP is conjugated to the morpholino oligomer by a linker selected from:

16. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and an antisense compound, wherein the antisense compound comprises:

an antisense oligomer of 8-30 morpholino subunits linked together by phosphorodiamidate linkages, wherein:

each morpholino subunit is of a formula:

wherein each B is a base pairing moiety independently selected from adenine, cytosine, guanine, uracil, thymine or hypoxanthine, wherein each B taken together comprises a sequence of at least 8 contiguous bases that is complementary to: (i) the polyCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in Myotonic dystrophy type 1 (DM1) or (ii) the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in Myotonic dystrophy type 2 (DM2); and

each phosphorodiamidate linkage is of a formula:

 and

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

the CPP is of a formula selected from the group consisting of:

wherein independently for each instance R a is H or acetyl, and the CPP is conjugated to the morpholino oligomer by a linker selected from: