COMPOSITIONS FOR TREATING MUSCULAR DYSTROPHY
Improved compositions and methods for treating muscular dystrophy by administering antisense molecules capable of binding to a selected target site in the human dystrophin gene to induce exon skipping are described.
1 . A method of treating Duchenne muscular dystrophy or Becker muscular dystrophy in a human subject comprising administering about 30 mg/kg to about 50 mg/kg of a composition comprising an antisense oligonucleotide of 20 to 50 nucleotides in length comprising at least 10 consecutive nucleotides complementary to a target region in an exon of the human dystrophin gene, wherein the antisense oligonucleotide specifically hybridizes to the target region inducing exon skipping, thereby treating Duchenne muscular dystrophy or Becker muscular dystrophy in the subject.
2 . The method of claim 1 , wherein treatment increases the number of dystrophin-positive fibers to at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of normal in the subject.
3 . The method of claim 2 , wherein the number of dystrophin-positive fibers is increased to between 20-60% of normal in the human subject.
4 . The method of claim 2 , wherein the number of dystrophin-positive fibers is increased to between 30-50% of normal in the human subject.
5 . The method of claim 1 , wherein about 30 mg/kg of the composition is administered to the human subject.
6 . The method of claim 1 , wherein about 50 mg/kg of the composition is administered to the human subject.
7 . The method of claim 1 , wherein treatment improves or maintains a stable walking distance in a 6 minute walk test from a 20% deficit in the subject relative to a healthy peer.
8 . The method of claim 1 , wherein the antisense oligonucleotide is substantially uncharged.
9 . The method of claim 1 , wherein the antisense oligonucleotide comprises morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of an adjacent subunit.
10 . The method of claim 1 , wherein the antisense oligonucleotide comprises morpholino subunits linked by substantially uncharged phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of an adjacent subunit.
11 . The method of claim 1 , wherein the antisense oligonucleotide comprises morpholino subunits and phosphorodiamidate intersubunit linkages.
12 . The method of claim 1 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution, or cellular uptake of the antisense oligonucleotide.
13 . The method of claim 12 , wherein the antisense oligonucleotide is conjugated to an arginine-rich peptide.
14 . The method of claim 1 , wherein the antisense oligonucleotide is 30 to 50 nucleotides in length.
15 . The method of claim 1 , wherein the antisense oligonucleotide is 20 to 30 nucleotides in length.
16 . The method of claim 1 , wherein the exon in the human dystrophin gene is selected from the group consisting of exon 51, exon 50, exon 53, exon 45, exon 46, exon 44, exon 52, exon 55 and exon 8.
17 . The method of claim 1 , wherein the antisense oligonucleotide is selected from the group consisting of SEQ ID NOS: 1-9.
18 . The method of claim 1 , wherein the antisense oligonucleotide is SEQ ID NO: 1.
19 . The method of claim 1 , wherein the antisense oligonucleotide is any one or a combination of the nucleotide sequences set forth in Tables 3 and 4, wherein uracil bases in the antisense oligonucleotide are optionally thymine bases.
20 . The method of claim 1 , wherein the composition further comprises phosphate-buffered saline.
21 . The method of claim 1 , wherein the composition is administered by systemic administration.
22 . The method of claim 1 , wherein the composition is administered once weekly by infusion.
23 . The method of claim 1 , further comprising administering a steroid to the human subject.