Compositions and methods for modulation of smn2 splicing in a subject

Abstract

Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a subject. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders, including spinal muscular atrophy.

1 . A method comprising administering to a subject an antisense compound comprising an antisense oligonucleotide complementary to intron 7 of a nucleic acid encoding human SMN2 pre-mRNA, wherein the antisense compound is administered into the cerebrospinal fluid. 
     
     
         2 . The method of  claim 1 , wherein the administration is: (i) into the intrathecal space; (ii) into the cerebrospinal fluid in the brain. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the administration comprises a bolus injection. 
     
     
         5 .- 14 . (canceled) 
     
     
         15 . The method of  claim 1  comprising administering at least one induction dose during an induction phase and administering at least one maintenance dose during a maintenance phase. 
     
     
         16 .- 32 . (canceled) 
     
     
         33 . The method of  claim 1 , comprising co-administration of the antisense compound and at least one other therapy. 
     
     
         34 .- 41 . (canceled) 
     
     
         42 . The method of  claim 1 , wherein (i) inclusion of exon 7 of SMN2 mRNA in a motoneuron in the subject is increased; or (ii) inclusion of exon 7 amino acids in SMN2 polypeptide in a motoneuron in the subject is increased. 
     
     
         43 . (canceled) 
     
     
         44 . A method of increasing (i) inclusion of exon 7 of SMN2 mRNA in a motoneuron in a subject or (ii) increasing inclusion of exon 7 amino acids in SMN2 polypeptide in a motoneuron in a subject, the method comprising administering to the subject an antisense compound comprising an antisense oligonucleotide complementary to intron 7 of a nucleic acid encoding human SMN2 and thereby increasing inclusion of exon 7 of SMN2 mRNA in the motoneuron in the subject or increasing inclusion of exon 7 amino acids in SMN2 polypeptide in a motoneuron in the subject. 
     
     
         45 . (canceled) 
     
     
         46 . The method of  claim 44 , wherein the subject has SMA. 
     
     
         47 . The method of  claim 44 , wherein the subject has type I SMA, type II SMA, or type III SMA. 
     
     
         48 .- 49 . (canceled) 
     
     
         50 . The method of  claim 44 , wherein a first dose is administered in utero. 
     
     
         51 . The method of  claim 50 , wherein the first dose is administered prior to complete formation of the blood-brain-barrier. 
     
     
         52 .- 60 . (canceled) 
     
     
         61 . The method of  claim 1 , further comprising identifying a subject having SMA. 
     
     
         62 .- 84 . (canceled) 
     
     
         85 . The method of  claim 1 , wherein each nucleoside of the antisense oligonucleotide comprises a 2′-methoxyethyl sugar moiety. 
     
     
         86 . (canceled) 
     
     
         87 . The method of  claim 1 , wherein each internucleoside linkage of the antisense oligonucleotide is a phosphorothioate internucleoside linkage. 
     
     
         88 . The method of  claim 1 , wherein the antisense oligonucleotide consists of 10 to 25 linked nucleosides. 
     
     
         89 .- 93 . (canceled) 
     
     
         94 . The method of  claim 1 , wherein the oligonucleotide has a nucleobase sequence comprising at least 10 contiguous nucleobases of the nucleobase sequence SEQ ID NO: 1. 
     
     
         95 . The method of  claim 94 , wherein the oligonucleotide has a nucleobase sequence comprising at least 15 contiguous nucleobases of the nucleobase sequence SEQ ID NO: 1. 
     
     
         96 .- 103 . (canceled) 
     
     
         104 . An antisense compound comprising an antisense oligonucleotide complementary to intron 7 of a nucleic acid encoding human SMN2. 
     
     
         105 .- 107 . (canceled) 
     
     
         108 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, the antisense compound of  claim 104 , and one or more of: valproic acid, riluzole, hydroxyurea, a butyrate, and trichostatin-A.