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 first and second chemically synthesized oligomeric compounds, wherein:
the first oligomeric compound is fully complementary to and capable of hybridizing with said second oligomeric compound and to a selected nucleic acid target;
at least one of said first and second oligomeric compounds comprises a contiguous sequence of linked nucleosides wherein the sequence defines an alternating motif having the formula:
5′-Q(-L-Z-L-Q) n (-L-Z) nn -3′
wherein:
each L is an internucleoside linking group;
each Q is a nucleoside having a 2′-F substituent group and each Z is a β-D-deoxyribonucleoside; or
each Q is β-D-deoxyribonucleoside and each Z is a nucleoside having a 2′-F substituent group;
n is from about 8 to about 14 and nn is 0 or 1; and
each of said oligomeric compounds is from 12 to 30 linked nucleosides in length.
2. The composition of claim 1 wherein only one of said first and said second oligomeric compounds comprises said alternating motif.
3. The composition of claim 1 wherein both of said first and said second oligomeric compounds independently comprise said alternating motif.
4. The composition of claim 1 wherein each Z is a β-D-deoxyribonucleoside.
5. The composition of claim 1 wherein said first oligomeric compound further comprises a 5′-phosphate group.
6. The composition of claim 1 wherein said second oligomeric compound further comprises a 5′-phosphate group.
7. The composition of claim 1 wherein each of said first and said second oligomeric compounds independently, comprise a 5′-phosphate group.
8. The composition of claim 1 wherein said first oligomeric compound comprises a 3′-terminal OH group.
9. 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.
10. The composition of claim 1 wherein the nucleosides of each of said first and said second oligomeric compounds are linked by phosphorothioate internucleoside linking groups.
11. The composition of claim 1 wherein the nucleosides of one said first and said second oligomeric compound are linked by phosphorothioate internucleoside linking groups and the nucleosides of the other of said first and said second oligomeric compound are linked by phosphodiester internucleoside linking groups.
12. The composition of claim 1 wherein the nucleosides of said first oligomeric compound are linked by phosphorothioate internucleoside linking groups and the nucleosides of said second oligomeric compound are linked by phosphodiester internucleoside linking groups.
13. The composition of claim 1 wherein each of the nucleosides of said first and said second oligomeric compound are independently linked by phosphorothioate or phosphodiester internucleoside linking groups.
14. The composition of claim 1 wherein each of the nucleosides of said first and said second oligomeric compound are independently linked by an internucleoside linking group selected from the group consisting of phosphodiester, phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl phosphonate, alkyl phosphonate, 5′-alkylene phosphonate, chiral phosphonate, phosphinate, phosphoramidate, 3′-amino phosphoramidate, aminoalkylphosphoramidate, thionophosphoramidate, thionoalkylphosphonate, thionoalkylphosphotriester, selenophosphate and boranophosphate.
15. The composition of claim 1 further comprising at least one conjugate group.
16. 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.
17. The composition of claim 16 wherein said terminal cap moiety is an inverted deoxy abasic moiety.
18. The composition of claim 16 wherein one of said first and second oligomeric compounds is a sense strand and wherein said sense strand comprises a terminal cap moiety at one or both of the 3′-terminal and the 5′-terminal ends.
19. The composition of claim 18 wherein said terminal cap moiety is an inverted deoxy abasic moiety.
20. The composition of claim 1 wherein said first and said second oligomeric compounds are a complementary pair of siRNA oligoribonucleotides.
21. The composition of claim 1 wherein each of said first and second oligomeric compounds has from 21 to 24 nucleosides.
22. The composition of claim 1 wherein said first oligomeric compound is an antisense oligonucleotide.
23. The composition of claim 1 wherein said second oligomeric compound is a sense oligonucleotide.
24. The composition of claim 1 further comprising one or more overhangs.