2'-methoxy substituted oligomeric compounds and compositions for use in gene modulations

Abstract

Compositions comprising first and second oligomers are provided wherein at least a portion of the first oligomer is capable of hybridizing with at least a portion of the second oligomer, at least a portion of the first oligomer is complementary to and capable of hybridizing to a selected target nucleic acid, and at least one of the first or second oligomers includes a modified sugar and/or backbone modification. In some embodiments the modification is a 2′-OCH3 substituent group on a sugar moiety. Oligomer/protein compositions are also provided comprising an oligomer complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein comprising at least a portion of an RNA-induced silencing complex (RISC), wherein at least one nucleotide of the oligomer has a modified sugar and/or backbone modification.

1 . A method for assessing the activity of an oligomeric compound comprising contacting the oligomeric compound with a cell in vitro, wherein the oligomeric compound comprises a first oligomer and a second oligomer, wherein:
 at least a portion of said first oligomer is capable of hybridizing with at least a portion of said second oligomer,   at least a portion of said first oligomer is complementary to and capable of hybridizing with a selected target nucleic acid,   each of said first and second oligomers is a chimeric oligomer,   wherein the second oligomer has an internal segment comprising at least four consecutive nucleosides each having a 2′-OCH 3  substituent group, and   wherein the chimeric oligomers are not a gapmers;   
       measuring or detecting a phenotypic change in the cell in vitro; and 
       thereby assessing the activity of the oligomeric compound. 
     
     
         2 . The method of  claim 1  wherein each of said first and second oligomers comprise from about 18 to about 30 linked nucleosides. 
     
     
         3 . The method of  claim 1  wherein each of said first and second oligomers comprise from about 21 to about 24 linked nucleosides. 
     
     
         4 . The method of  claim 1  wherein each of said first and second oligomers comprise 21 linked nucleosides. 
     
     
         5 . The method of  claim 1  wherein each of said first and second oligomers comprise nucleosides selected from β-D-ribonucleosides, 2′-OCH 3  modified nucleosides and 2′-deoxythymidine nucleosides. 
     
     
         6 . The method of  claim 1  wherein said first oligomer is an antisense oligomer and the second oligomer is a sense oligomer. 
     
     
         7 . The method of  claim 1  wherein said first and said second oligomers are a complementary pair of siRNA oligomers. 
     
     
         8 . The method of  claim 1  wherein each internucleoside linkage is, independently, a phosphodiester or phosphorothioate internucleoside linkage. 
     
     
         9 . The method of  claim 1  wherein each internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         10 . The method of  claim 1  wherein the 5′-terminal nucleoside of said first oligomer has a 5′-phosphate group. 
     
     
         11 . The method of  claim 1  wherein at least one of said first and second oligomers comprises a nucleoside with a 2′-F substituent group. 
     
     
         12 . The method of  claim 1  wherein each of said first and second oligomers are blunt ended. 
     
     
         13 . The method of  claim 1  wherein at least one of said first or second oligomers has an overhang. 
     
     
         14 . The method of  claim 1  wherein each of said first and second oligomers independently comprises a 3′-overhang consisting of two deoxythymidine nucleosides. 
     
     
         15 . The method of  claim 1  wherein at least one of said first and second oligomers comprises a blockmer. 
     
     
         16 . The method of  claim 15  wherein the blockmer comprises an oligonucleoside having at least two consecutive nucleosides of a first type located immediately adjacent to at least one nucleoside of a second type and
 wherein said nucleosides of said first type are different from said nucleosides of said second type. 
 
     
     
         17 . The method of  claim 16  wherein each of said nucleosides of said first type includes a 2′-OCH 3  substituent group. 
     
     
         18 . The method of  claim 16  wherein the blockmer comprises an oligonucleoside having at least three consecutive nucleosides of said first type. 
     
     
         19 . The method of  claim 16  wherein the blockmer comprises an oligonucleoside having at least five consecutive nucleosides of said first type.