EXON SKIPPING OLIGOMER CONJUGATES FOR MUSCULAR DYSTROPHY
Antisense oligomer conjugates complementary to a selected target site in the human dystrophin gene to induce exon 53 skipping are described.
1 . An antisense oligomer conjugate of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
each Nu is a nucleobase which taken together form a targeting sequence; and
T is a moiety selected from:
R 1 is C 1 -C 6 alkyl;
wherein the targeting sequence is complementary to an exon 53 annealing site in the dystrophin pre-mRNA designated as H53A (+36+60).
2 . The antisense oligomer conjugate of claim 1 , wherein each Nu is independently selected from cytosine (C), guanine (G), thymine (T), adenine (A), 5-methylcytosine (5mC), uracil (U), and hypoxanthine (I).
3 . The antisense oligomer conjugate of claim 1 , wherein the targeting sequence is SEQ ID NO: 1 (5′-GTTGCCTCCGGTTCTGAAGGTGTTC-3′), wherein each thymine (T) is optionally uracil (U).
4 . The antisense oligomer conjugate of claim 1 , wherein T is
and the targeting sequence is SEQ ID NO: 1 (5′-GTTGCCTCCGGTTCTGAAGGTGTTC-3′), wherein each thymine (T) is optionally uracil (U).
5 . The antisense oligomer conjugate of claim 1 , wherein T is
and the targeting sequence is SEQ ID NO: 1 (5′-GTTGCCTCCGGTTCTGAAGGTGTTC-3′).
6 - 11 . (canceled)
12 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13 . 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 53 skipping, the method comprising administering to the subject the antisense oligomer conjugate of claim 1 .
14 . The method of claim 13 , wherein the antisense oligomer conjugate is administered weekly, biweekly, or every third week.
15 . The method of claim 13 , wherein the antisense oligomer conjugate is administered monthly.
16 . 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 53 skipping, the method comprising administering to the subject the antisense oligomer conjugate of claim 1 .
17 . The method of claim 16 , wherein the antisense oligomer conjugate is administered weekly, biweekly, every third week, or monthly.
18 - 20 . (canceled)
21 . The method of claim 16 , wherein the antisense oligomer conjugate is administered at a dose of about 30 mg/kg.
22 . The method of claim 16 , wherein the antisense oligomer conjugate is administered at a dose of about 40 mg/kg.
23 . The method of claim 16 , wherein the antisense oligomer conjugate is administered at a dose of about 60 mg/kg.
24 . The method of claim 16 , wherein the antisense oligomer conjugate is administered at a dose of about 80 mg/kg.
25 . The method of claim 16 , wherein the antisense oligomer conjugate is administered at a dose of about 160 mg/kg.
26 . 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 53 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12 .
27 . 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 53 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12 .
28 . A method of excluding exon 53 from dystrophin pre-mRNA during mRNA processing in a subject having a mutation of the dystrophin gene that is amenable to exon 53 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12 .
29 . A method of binding exon 53 of dystrophin pre-mRNA in a subject having a mutation of the dystrophin gene that is amenable to exon 53 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12 .