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.

What is claimed is: 
     
         1 . A compound comprising a modified oligonucleotide consisting of 16-20 linked nucleosides, wherein the modified oligonucleotide is complementary to SMN2; and wherein each internucleoside linkage is either phosphorothioate or phosphodiester and at least one internucleoside linkage is phosphorothioate and at least one internucleoside linkage is phosphodiester. 
     
     
         2 . A compound comprising a modified oligonucleotide consisting of 16-20 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 and having 6 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         3 . A compound comprising a modified oligonucleotide, wherein the modified oligonucleotide has the nucleobase sequence of SEQ ID NO.: 1, wherein the modified oligonucleotide has 6 or more phosphodiester internucleoside linkages, and wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         4 . A compound comprising a modified oligonucleotide, wherein the modified oligonucleotide has the nucleobase sequence of SEQ ID NO.: 7, wherein the modified oligonucleotide has 6 or more phosphodiester internucleoside linkages, and wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         5 . A compound comprising a modified oligonucleotide, wherein the modified oligonucleotide has the nucleobase sequence of SEQ ID NO.: 2, wherein the modified oligonucleotide has 6 or more phosphodiester internucleoside linkages, and wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         6 . The compound of any of  claims 1  to  5 , having 7 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         7 . The compound of any of  claims 1  to  5 , having 8 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         8 . The compound of any of  claims 1  to  5 , having 9 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         9 . The compound of any of  claims 1  to  5 , having 10 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         10 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNoNoNoNsNsNsNoNoNoNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         11 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNoNoNoNoNoNoNoNsNsNsNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         12 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNoNsNsNsNoNsNsNsNoNsNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         13 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNoNsNsNoNsNsNoNsNsNoNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         14 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNsNoNsNoNsNoNsNoNsNoNsNoNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         15 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNoNoNoNsNsNsNsNsNsNsNsNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         16 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNoNsNoNsNoNsNoNsNoNsNoNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         17 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNoNsNoNsNoNsNoNsNoNsNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         18 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNoNoNsNoNoNsNoNoNsNoNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         19 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNoNoNoNoNsNsNsNsNsNsNsNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         20 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNoNoNoNoNsNsNsNsNsNsNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         21 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNoNoNoNoNoNsNsNsNsNsNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         22 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNoNoNoNoNoNsNsNsNsNoNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         23 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNsNoNoNoNoNoNoNoNoNoNoNoNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         24 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNsNsNoNoNoNoNoNoNoNoNoNoNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         25 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNsNsNoNoNoNoNoNoNoNoNoNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         26 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNsNsNsNoNoNoNoNoNoNoNoNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         27 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNsNsNsNoNoNoNoNoNoNoNsNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         28 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNsNsNsNsNoNoNoNoNoNoNsNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         29 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNsNsNsNsNoNoNoNoNoNsNsNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         30 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNoNoNoNsNsNsNsNsNsNsNsNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         31 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNsNoNoNoNoNoNoNoNoNoNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         32 . The compound of  claim 3 , wherein the modified oligonucleotide has an NsNoNsNoNsNoNsNoNsNoNsNoNsNoNsNoNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         33 . The compound of  claim 4 , wherein the modified oligonucleotide has an NsNoNsNoNsNoNsNoNsNoNsNoNsNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         34 . The compound of  claim 4 , wherein the modified oligonucleotide has an NsNoNoNsNoNsNsNoNsNsNoNsNsNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         35 . The compound of  claim 4 , wherein the modified oligonucleotide has an NsNoNsNsNoNsNsNoNsNsNoNsNsNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         36 . The compound of  claim 4 , wherein the modified oligonucleotide has an NsNoNsNsNoNsNsNoNsNsNoNsNsNoNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         37 . The compound of  claim 4 , wherein the modified oligonucleotide has an NsNoNsNsNoNsNsNsNoNsNsNsNoNsNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         38 . The compound of  claim 4 , wherein the modified oligonucleotide has an NsNoNsNsNsNsNoNsNsNsNsNoNsNsNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         39 . The compound of  claim 5 , wherein the modified oligonucleotide has an NsNoNsNoNsNoNsNoNsNoNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         40 . The compound of  claim 5 , wherein the modified oligonucleotide has an NsNsNoNsNsNoNsNsNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         41 . The compound of  claim 5 , wherein the modified oligonucleotide has an NsNsNoNsNsNoNsNsNoNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         42 . The compound of  claim 5 , wherein the modified oligonucleotide has an NsNsNsNoNsNsNsNoNsNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         43 . The compound of  claim 5 , wherein the modified oligonucleotide has an NsNsNsNsNoNsNsNsNsNoNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         44 . The compound of any of  claims 1  to  43 , wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety, and wherein each modified sugar moiety comprises a 2′-methoxyethyl modification. 
     
     
         45 . A pharmaceutical composition comprising the compound of any of  claims 1  to  44 . 
     
     
         46 . A method of promoting inclusion of exon 7 in SMN2 transcripts in a cell, tissue or organ, comprising contacting said cell, tissue or organ with the compound of any of  claims 1  to  44  or the composition of  claim 45 . 
     
     
         47 . A method of treating Spinal Muscular Atrophy Type I, comprising administering the compound of any of  claims 1  to  44  or the composition of  claim 45  to a patient in need thereof. 
     
     
         48 . A method of treating Spinal Muscular Atrophy Type II, comprising administering the compound of any of  claims 1  to  44  or the composition of  claim 45  to a patient in need thereof. 
     
     
         49 . A method of treating Spinal Muscular Atrophy Type III, comprising administering the compound of any of  claims 1  to  44  or the composition of  claim 45  to a patient in need thereof. 
     
     
         50 . A method of treating Spinal Muscular Atrophy Type IV, comprising administering the compound of any of  claims 1  to  44  or the composition of  claim 45  to a patient in need thereof. 
     
     
         51 . An antisense oligonucleotide of any of  claims 1  to  44  or the composition of  claim 45  for use in therapy. 
     
     
         52 . Use of an antisense oligonucleotide of any of  claims 1  to  44  or the composition of  claim 45  for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type I. 
     
     
         53 . Use of an antisense oligonucleotide of any of  claims 1  to  44  or the composition of  claim 45  for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type II 
     
     
         54 . Use of an antisense oligonucleotide of any of  claims 1  to  44  or the composition of  claim 45  for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type III. 
     
     
         55 . Use of an antisense oligonucleotide of any of  claims 1  to  44  or the composition of  claim 45  for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type IV. 
     
     
         56 . Use of an antisense oligonucleotide of any of  claims 1  to  45  for the preparation of a medicament for the treatment of spinal muscular atrophy. 
     
     
         57 . A compound comprising a modified oligonucleotide consisting of 16-20 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, or 27 and having 6 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         58 . The compound of  claim 57 , having 7 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         59 . The compound of  claim 57 , having 8 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         60 . The compound of  claim 57 , having 9 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         61 . The compound of  claim 57 , having 10 or more phosphodiester internucleoside linkages, wherein each internucleoside linkage that is not a phosphodiester internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         62 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNoNoNoNsNsNsNoNoNoNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         63 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNoNoNoNoNoNoNoNsNsNsNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         64 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNoNsNsNsNoNsNsNsNoNsNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         65 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNoNsNsNoNsNsNoNsNsNoNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         66 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNoNsNoNsNoNsNoNsNoNsNoNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         67 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNoNoNsNsNsNsNsNsNsNsNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         68 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNoNsNoNsNoNsNoNsNoNsNoNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         69 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNoNsNoNsNoNsNoNsNoNsNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         70 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNoNsNoNoNsNoNoNsNoNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         71 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNoNoNoNsNsNsNsNsNsNsNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         72 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNoNoNoNsNsNsNsNsNsNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         73 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNoNoNoNoNsNsNsNsNsNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         74 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNoNoNoNoNsNsNsNsNoNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         75 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNoNoNoNoNoNoNoNoNoNoNoNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         76 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNsNoNoNoNoNoNoNoNoNoNoNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         77 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNsNoNoNoNoNoNoNoNoNoNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         78 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNsNsNoNoNoNoNoNoNoNoNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         79 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNsNsNoNoNoNoNoNoNoNsNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         80 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNsNsNsNoNoNoNoNoNoNsNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         81 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNsNsNsNoNoNoNoNoNsNsNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         82 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNoNoNsNsNsNsNsNsNsNsNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         83 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNoNoNoNoNoNoNoNoNoNoNoNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         84 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNsNoNsNoNsNoNsNoNsNoNsNoNsNoNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         85 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNsNoNsNoNsNoNsNoNsNoNsNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         86 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNoNsNoNsNsNoNsNsNoNsNsNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         87 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNsNsNoNsNsNoNsNsNoNsNsNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         88 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNsNsNoNsNsNoNsNsNoNsNsNoNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         89 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNsNsNoNsNsNsNoNsNsNsNoNsNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         90 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNsNsNsNsNoNsNsNsNsNoNsNsNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         91 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNoNsNoNsNoNsNoNsNoNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         92 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNoNsNsNoNsNsNoNsNoNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         93 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNoNsNsNoNsNsNoNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         94 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNoNsNsNsNoNsNsNsNoNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         95 . The compound of  claim 57 , wherein the modified oligonucleotide has an NsNsNsNsNoNsNsNsNsNoNsNsNsNsN internucleoside motif, wherein each “N” represents a nucleobase, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage. 
     
     
         96 . The compound of any of  claims 57  to  95 , wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety, and wherein each modified sugar moiety comprises a 2′-methoxyethyl modification. 
     
     
         97 . A pharmaceutical composition comprising the compound of any of  claims 57  to  96 . 
     
     
         98 . A method of promoting inclusion of exon 7 in SMN2 transcripts in a cell, tissue or organ, comprising contacting said cell, tissue or organ with the compound of any of  claims 57  to  95  or the composition of  claim 96 . 
     
     
         99 . A method of treating Spinal Muscular Atrophy Type I, comprising administering the compound of any of  claims 57  to  95  or the composition of  claim 96  to a patient in need thereof. 
     
     
         100 . A method of treating Spinal Muscular Atrophy Type II, comprising administering the compound of any of  claims 57  to  95  or the composition of  claim 96  to a patient in need thereof. 
     
     
         101 . A method of treating Spinal Muscular Atrophy Type III, comprising administering the compound of any of  claims 57  to  95  or the composition of  claim 96  to a patient in need thereof. 
     
     
         102 . A method of treating Spinal Muscular Atrophy Type IV, comprising administering the compound of any of  claims 57  to  95  or the composition of  claim 96  to a patient in need thereof. 
     
     
         103 . An antisense oligonucleotide of any of  claims 57  to  95  or the composition of  claim 96  for use in therapy. 
     
     
         104 . Use of an antisense oligonucleotide of any of  claims 57  to  95  or the composition of  claim 96  for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type I. 
     
     
         105 . Use of an antisense oligonucleotide of any of  claims 57  to  95  or the composition of  claim 96  for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type II 
     
     
         106 . Use of an antisense oligonucleotide of any of  claims 57  to  95  or the composition of  claim 96  for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type III. 
     
     
         107 . Use of an antisense oligonucleotide of any of  claims 57  to  95  or the composition of  claim 96  for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type IV. 
     
     
         108 . Use of an antisense oligonucleotide of any of  claims 57  to  96  for the preparation of a medicament for the treatment of spinal muscular atrophy.