Compounds and methods for modulating smn2

Abstract

Provided are compounds, methods, and pharmaceutical compositions for modulating SMN2 RNA and/or protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a neurodegenerative disorder. Such symptoms include reduced muscle strength; inability or reduced ability to sit upright, to stand, and/or walk; reduced neuromuscular activity; reduced electrical activity in one or more muscles; reduced respiration; inability or reduced ability to eat, drink, and/or breathe without assistance; loss of weight or reduced weight gain; and/or decreased survival.

1 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         2 . The modified oligonucleotide of  claim 1 , which is the sodium salt or the potassium salt. 
     
     
         3 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A chirally enriched population of modified oligonucleotides of  claim 1 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration. 
     
     
         5 . The chirally enriched population of  claim 1 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration. 
     
     
         6 . The chirally enriched population of  claim 1 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration. 
     
     
         7 . The chirally enriched population of  claim 1 , wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage. 
     
     
         8 . The chirally enriched population of  claim 1 , wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each phosphorothioate internucleoside linkage or for modified oligonucleotides having the (Rp) configuration at each phosphorothioate internucleoside linkage. 
     
     
         9 . The chirally enriched population of  claim 1 , wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages. 
     
     
         10 . The chirally enriched population of  claim 1 , wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5′ to 3′ direction. 
     
     
         11 . A population of modified oligonucleotides of  claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         12 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:  m C ns  A no    m C ns  T no  T ns  T ns    m C ns  A ns  T ns  A ns  A ns  T ns  G ns    m C ns  T ns  G ns  G ns    m C n  (SEQ ID NO: 21), wherein:
 A=an adenine nucleobase,     m C=a 5-methyl cytosine nucleobase,   G=a guanine nucleobase,   T=a thymine nucleobase,   n=a 2′-NMA sugar moiety,   s=a phosphorothioate internucleoside linkage, and   o=a phosphodiester internucleoside linkage.   
     
     
         13 . The oligomeric compound of  claim 12 , wherein the modified oligonucleotide is linked to a conjugate group. 
     
     
         14 . A pharmaceutical composition comprising the modified oligonucleotide of  claim 1  and a pharmaceutically acceptable diluent or carrier. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial CSF (aCSF) or PBS. 
     
     
         17 . A pharmaceutical composition comprising the modified oligonucleotide of  claim 3  and a pharmaceutically acceptable diluent or carrier. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial CSF (aCSF) or PBS. 
     
     
         20 . A pharmaceutical composition comprising the oligomeric compound of  claim 12  and a pharmaceutically acceptable diluent or carrier. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and artificial CSF (aCSF) or PBS. 
     
     
         23 . A pharmaceutical composition comprising the population of modified oligonucleotides of  claim 4 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and artificial CSF (aCSF) or PBS. 
     
     
         26 . A method of treating a disease associated with SMN1 or SMN2 comprising administering to a subject having or at risk for developing a disease associated with SMN1 or SMN2 a therapeutically effective amount of a pharmaceutical composition according to  claim 14 ; thereby treating the disease associated with SMN1 or SMN2. 
     
     
         27 . A method of treating a disease associated with SMN1 or SMN2 comprising administering to a subject having or at risk for developing a disease associated with SMN1 or SMN2 a therapeutically effective amount of a pharmaceutical composition according to  claim 17 ; thereby treating the disease associated with SMN1 or SMN2. 
     
     
         28 . A method of treating a disease associated with SMN1 or SMN2 comprising administering to a subject having or at risk for developing a disease associated with SMN1 or SMN2 a therapeutically effective amount of a pharmaceutical composition according to  claim 20 ; thereby treating the disease associated with SMN1 or SMN2. 
     
     
         29 . The method of  claim 26 , wherein the disease is any of Type I SMA, Type II SMA, Type III SMA, or Type IV SMA. 
     
     
         30 . The method of  claim 29 , wherein at least one symptom of SMA is ameliorated. 
     
     
         31 . The method of  claim 30 , wherein the symptom is any of reduced muscle strength; inability or reduced ability to sit upright, to stand, and/or walk; reduced neuromuscular activity; reduced electrical activity in one or more muscles; reduced respiration; inability or reduced ability to eat, drink, and/or breathe without assistance; loss of weight or reduced weight gain; and/or decreased survival.