Exon skipping oligomer conjugates for muscular dystrophy
Antisense oligomer conjugates complementary to a selected target site in the human dystrophin gene to induce exon 52 skipping are described.
1. A method for treating Duchenne muscular dystrophy (DMD) in a subject in need thereof wherein the subject has a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject an antisense oligomer conjugate of Formula (IV):
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the antisense oligomer conjugate is of Formula (IVA):
3. A method of restoring an mRNA reading frame to induce dystrophin production in a subject having a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject an antisense oligomer conjugate of Formula (IV):
or a pharmaceutically acceptable salt thereof.
4. The method of claim 3 , wherein the antisense oligomer conjugate is of Formula (IVA):
5. A method for treating Duchenne muscular dystrophy (DMD) in a subject in need thereof wherein the subject has a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject a pharmaceutical composition comprising an antisense oligomer conjugate of Formula (IV):
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. The method of claim 5 , wherein the antisense oligomer conjugate is of Formula (IVA):
7. A method of restoring an mRNA reading frame to induce dystrophin production in a subject having a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject a pharmaceutical composition comprising an antisense oligomer conjugate of Formula (IV):
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8. The method of claim 7 , wherein the antisense oligomer conjugate is of Formula (IVA):
9. A method of excluding exon 52 from dystrophin pre-mRNA during mRNA processing in a subject having a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject a pharmaceutical composition comprising an antisense oligomer conjugate of Formula (IV):
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. The method of claim 9 , wherein the antisense oligomer conjugate is of Formula (IVA):
11. A method of binding exon 52 of dystrophin pre-mRNA in a subject having a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject a pharmaceutical composition comprising an antisense oligomer conjugate of Formula (IV):
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. The method of claim 11 , wherein the antisense oligomer conjugate is of Formula (IVA):
13. The method of claim 1 , wherein the antisense oligomer conjugate is administered weekly.
14. The method of claim 1 , wherein the antisense oligomer conjugate is administered biweekly.
15. The method of claim 1 , wherein the antisense oligomer conjugate is administered every third week.
16. The method of claim 1 , wherein the antisense oligomer conjugate is administered monthly.
17. The method of claim 1 , wherein the antisense oligomer conjugate is administered at a dose selected from about 30 mg/kg, about 40 mg/kg, about 60 mg/kg, about 80 mg/kg, and about 160 mg/kg.
18. The method of claim 3 , wherein the antisense oligomer conjugate is administered weekly.
19. The method of claim 3 , wherein the antisense oligomer conjugate is administered biweekly.
20. The method of claim 3 , wherein the antisense oligomer conjugate is administered every third week.
21. The method of claim 3 , wherein the antisense oligomer conjugate is administered monthly.
22. The method of claim 3 , wherein the antisense oligomer conjugate is administered at a dose selected from about 30 mg/kg, about 40 mg/kg, about 60 mg/kg, about 80 mg/kg, and about 160 mg/kg.