Oligomeric compounds and methods
The present invention provides oligomeric compounds and uses thereof. In certain embodiments, such oligomeric compounds are useful as antisense compounds. Certain such antisense compounds are useful as RNase H antisense compounds or as RNAi compounds.
1. An oligomeric compound comprising an antisense oligonucleotide consisting of 16 to 30 linked nucleosides having the formula:
5′-Q-(E) w -(A) 2 -(B) x -(A) 2 -(C) y -(A) 3 -D
wherein:
each A is a 2′-OCH 3 modified nucleoside;
each E is, independently, a 2′-F or a 2′-OCH 3 modified nucleoside wherein at least the E that is linked to the adjacent 5′-A is a 2′-F modified nucleoside;
each B and C is a 2′-F modified nucleoside;
D is H or 3′-terminal group;
Q is a 5′-phosphate stabilizing nucleoside comprising:
i) a 5′-terminal modified phosphate; and
ii) a 2′-substituent group selected from F, O—(CH 2 ) 2 —O—CH 3 , and OCH 3 ;
w is from about 4 to about 10;
x is from about 2 to about 4; and
y is from about 3 to about 8.
2. The oligomeric compound of claim 1 wherein the 5′-terminal modified phosphate is selected from a phosphonate, alkylphosphonate, substituted alkylphosphonate, aminoalkyl phosphonate, substituted aminoalkyl phosphonate, phosphorothioate, phosphoramidate, alkylphosphonothioate, substituted alkylphosphonothioate, phosphorodithioate, and thiophosphoramidate.
3. The oligomeric compound of claim 2 wherein the 5′-terminal modified phosphate is selected from a phosphonate, alkylphosphonate and substituted alkylphosphonate.
4. The oligomeric compound of claim 1 wherein the 5′-phosphate stabilizing nucleoside comprises a 5′-substituent group selected from F and CH 3 .
5. The oligomeric compound of claim 1 wherein the 2′-substituent group is OCH 3 .
6. The oligomeric compound of claim 1 wherein each E is a 2′-F modified nucleoside.
7. The oligomeric compound of claim 1 wherein (E) w comprises from 1 to 4,2′-OH 3 modified nucleosides.
8. The oligomeric compound of claim 1 wherein w is from 5 to 9, x is from 2 to 3 and y is from 4 to 7 and the sum of w, x and y is from 11 to 19.
9. The oligomeric compound of claim 8 wherein w is from 5 to 9, x is 2 and y is from 5 to 6.
10. The oligomeric compound of claim 1 wherein D is a 3′-terminal group.
11. The oligomeric compound of claim 10 wherein the 3′-terminal group comprises two linked 2′-O—(CH 2 ) 2 —OCH 3 modified nucleosides.
12. The oligomeric compound of claim 11 wherein the two linked 2′-O—(CH 2 ) 2 —OCH 3 modified nucleosides are non-hybridizing nucleosides.
13. The oligomeric compound of claim 1 comprising at least one 3′-terminal group wherein said terminal group comprises a conjugate group.
14. The oligomeric compound of claim 1 wherein each internucleoside linking group linking said linked nucleosides is, independently, a phosphorothioate internucleoside linking group or a phosphodiester internucleoside linking group.
15. The oligomeric compound of claim 1 wherein each internucleoside linking group linking said linked nucleosides is a phosphorothioate internucleoside linking group.
16. The oligomeric compound of claim 1 wherein each internucleoside linking group between adjacent A groups is a phosphodiester internucleoside linking group.
17. The oligomeric compound of claim 1 wherein the oligomeric compound is an RNAi or microRNA compound.
18. A pharmaceutical composition comprising an oligomeric compound according to claim 1 and a pharmaceutically acceptable diluent or carrier.
19. A method of inhibiting gene expression comprising contacting one or more cells with an oligomeric compound of claim 1 wherein said oligomeric compound is complementary to a target RNA.
20. The method of claim 19 , wherein the one or more cells are in vitro.
21. The method of claim 19 , wherein the one or more cells are in an animal.