Compositions comprising alternating 2′-modified nucleosides for use in gene modulation
The present invention provides compositions comprising at least one oligomeric compound comprising an alternating motif and further include a region that is complementary to a nucleic acid target. The compositions are useful for targeting selected nucleic acid molecules and modulating the expression of one or more genes. In preferred embodiments the compositions of the present invention hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA. The present invention also provides methods for modulating gene expression.
1. A composition comprising a first oligomeric compound and a second oligomeric compound, wherein:
each of said first and second oligomeric compound has from about 18 to about 30 nucleotides and said first oligomeric compound is capable of hybridizing with said second oligomeric compound;
said first oligomeric compound is complementary to and capable of hybridizing to a selected nucleic acid target; and
said first oligomeric compound comprises at least
one motif selected from F(SF) n S nn where n is from 2 to about 20, nn is 0 or 1, one of F and S is a 2′—F modified nucleoside and the other of F and S is a 2′—O—CH 3 modified nucleoside.
2. The composition of claim 1 wherein said first oligomeric compound further comprises a 5′-phosphate group.
3. The composition of claim 1 wherein said second oligomeric compound further comprises a 5′-phosphate group.
4. The composition of claim 1 wherein the nucleosides of each of said first and said second oligomeric compounds are linked by phosphodiester internucleoside linking groups.
5. The composition of claim 1 wherein each of the nucleosides of said first and said second oligomeric compounds are independently linked by phosphoro-thioate or phosphodiester internucleoside linking groups.
6. The composition of claim 1 wherein said first oligomeric compound comprises one of said F(SF) n S nn motifs.
7. The composition of claim 1 wherein said second oligomeric compound comprises at least one motif selected from F(SF) n S nn where n is from 2 to about 20 and nn is 0 or 1.
8. The composition of claim 7 wherein said first oligomeric compound has an F starting at its 5′-terminus which hybridizes to an S on the 3′-terminus of said second oligomeric compound when said first and said second oligomeric compounds are hybridized.
9. The composition of claim 1 wherein at least one of said first and said second oligomeric compounds comprises one 3′ or 5′-conjugate group.
10. The composition of claim 1 wherein at least one of said first and said second oligomeric compounds further comprises at least one terminal cap moiety attached at the 3′-end, the 5′-end or both the 3′-end and the 5′-end.
11. The composition of claim 10 wherein said terminal cap moiety is an inverted deoxy abasic moiety.
12. The composition of claim 1 wherein said first oligomeric compound comprises at least two of said F(SF) n S nn motifs.
13. The composition of claim 12 wherein said two motifs are separated by a region comprising a sequence of nucleosides.
14. The composition of claim 13 wherein one of said two motifs is located at the 5′-end and the second of said two motifs is located at the 3′-end and wherein from about 6 to about 20 nucleosides are located between said motifs.
15. The composition of claim 12 wherein said second oligomeric compound comprises at least two of said F(SF) n S nn motifs and said first oligomeric compound has an F starting at its 5′-terminus which hybridizes to an S on the 3′-terminus of said second oligomeric compound when said first and said second oligomeric compounds are hybridized.
16. The composition of claim 1 wherein each of said first and second oligomeric compounds has from about 21 to about 24 nucleotides.
17. A pharmaceutical composition or formulation comprising the composition of claim 1 .
18. A method of inhibiting gene expression comprising contacting one or more cells, a tissue, or an animal cell with the composition of claim 1 .
19. The composition of claim 1 wherein one or more of the terminal ends of the first and second oligomeric compounds comprises additional non-hybridizing nucleosides that form one or more overhangs.