Exon skipping compositions for treating muscular dystrophy

Abstract

Antisense molecules capable of binding to a selected target site in the human dystrophin gene to induce exon 44 skipping are described.

1 . An antisense oligonucleotide of 20 to 50 bases in length comprising at least 10 consecutive bases of a sequence selected from the group consisting of: SEQ ID NOs: 1-7, wherein the oligonucleotide specifically hybridizes to an exon 44 target region of the human dystrophin pre-mRNA, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide induces exon 44 skipping, and wherein thymine bases are optionally uracil bases;
 or a pharmaceutically acceptable salt thereof.   
     
     
         2 . The antisense oligonucleotide of  claim 1 , comprising a base sequence selected from the group consisting of SEQ ID NOs: 1-7. 
     
     
         3 . The antisense oligonucleotide of  claim 1 , consisting of a base sequence selected from the group consisting of SEQ ID NOs: 1-7. 
     
     
         4 - 14 . (canceled) 
     
     
         15 . The antisense oligonucleotide of  claim 3 , wherein the oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution, or cellular uptake of the antisense oligonucleotide. 
     
     
         16 . (canceled) 
     
     
         17 . The antisense oligonucleotide of  claim 15 , wherein the oligonucleotide is chemically linked to a polyethylene glycol moiety. 
     
     
         18 . An antisense oligonucleotide of 20 to 50 bases in length comprising at least 10 consecutive bases of a base sequence complementary to an exon 44 target region of the human dystrophin pre-mRNA designated as an annealing site selected from the group consisting of: H44A(−07+17), H44A(−07+20), H44A(−07+22), H44A(+77+101), H44A(+64+91), H44A(+62+89), and H44A(+62+85), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide induces exon 44 skipping;
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         19 . The antisense oligonucleotide of  claim 18 , wherein the antisense oligonucleotide is 20 to 30 bases in length. 
     
     
         20 . The antisense oligonucleotide of  claim 19 , wherein in the base sequence the thymine bases are uracil bases. 
     
     
         21 - 31 . (canceled) 
     
     
         32 . The antisense oligonucleotide of  claim 20 , wherein the oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution, or cellular uptake of the antisense oligonucleotide. 
     
     
         33 . (canceled) 
     
     
         34 . The antisense oligonucleotide of  claim 32 , wherein the oligonucleotide is chemically linked to a polyethylene glycol moiety. 
     
     
         35 - 37 . (canceled) 
     
     
         38 . A pharmaceutical composition, comprising an antisense oligonucleotide of  claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         39 . A method of treating Duchenne muscular dystrophy in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of  claim 38 . 
     
     
         40 - 42 . (canceled) 
     
     
         43 . A pharmaceutical composition, comprising an antisense oligonucleotide of  claim 18 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         44 . A method of treating Duchenne muscular dystrophy in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of  claim 43 .