Oligomeric compounds comprising bicyclic nucleotides and uses thereof
The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.
1. A compound comprising:
a modified oligonucleotide consisting of 17 to 20 linked nucleosides, wherein the modified oligonucleotide has a motif selected from e-e-e-k-(D) 9 -k-e-e-e, e-e-e-k-k-(D) 8 -e-e-e-e, e-k-e-k-(D) 9 -e-e-e-e, e-k-e-k-d-k-(D) 7 -e-e-e-e, k-d-k-d-k-(D) 10 -e-e-e-e-e, k-d-k-d-k-(D) 8 -e-e-e-e-e, and k-d-k-d-k-(D) 8 -e-e-e-e; and
wherein each “k” is a bicyclic nucleoside, each “e” is a 2′-substituted nucleoside, each “d” is a 2′-deoxynucleoside, and each “D” is a 2′-deoxynucleoside; and
wherein each 2′ -substitutent is selected from 2′-OMe, 2′-O-methoxyethyl, and 2′-F; and
wherein the nucleobase sequence of the modified oligonucleotide is complementary to the nucleobase sequence of a target nucleic acid.
2. The compound of claim 1 , wherein each 2′-substituent is a 2′-O-methoxyethyl group.
3. The compound of claim 1 , wherein the compound comprises a modified oligonucleotide having the motif: e-e-e-k-(D) 9 -k-e-e-e, wherein each “k” is a constrained ethyl nucleoside, each “e” is a 2′-MOE substituted nucleoside, and each “D” is a 2′-deoxynucleoside.
4. The compound of claim 1 , wherein the compound comprises a modified oligonucleotide having the motif: e-e-e-k-k-(D) 8 -e-e-e-e, wherein each “k” is a constrained ethyl nucleoside, each “e” is a 2′-MOE substituted nucleoside, and each “D” is a 2′-deoxynucleoside.
5. The compound of claim 1 , wherein the compound comprises a modified oligonucleotide having the motif: e-k-e-k-(D)9-e-e-e-e, wherein each “k” is a constrained ethyl nucleoside, each “e” is a 2′-MOE substituted nucleoside, and each “D” is a 2′-deoxynucleoside.
6. The compound of claim 1 , wherein the compound comprises a modified oligonucleotide having the motif: e-k-e-k-d-k-(D)7-e-e-e-e, wherein each “k” is a constrained ethyl nucleoside, each “e” is a 2′-MOE substituted nucleoside, each “d” is a 2′-deoxynucleoside, and each “D” is comprises a 2′-deoxynucleoside.
7. The compound of claim 1 , wherein the compound comprises a modified oligonucleotide having the motif: k-d-k-d-k-(D) 10 -e-e-e-e-e, wherein each “k” is a constrained ethyl nucleoside, each “e” is a 2′-MOE substituted nucleoside, each “d” is a 2′-deoxynucleoside, and each “D” is a 2′-deoxynucleoside.
8. The compound of claim 1 , wherein the compound comprises a modified oligonucleotide having the motif: k-d-k-d-k-(D) 8 -e-e-e-e-e, wherein each “k” is a constrained ethyl nucleoside, each “e” is a 2′-MOE substituted nucleoside, each “d” is a 2′-deoxynucleoside, and each “D” is a 2′-deoxynucleoside.
9. The compound of claim 1 , wherein the compound comprises a modified oligonucleotide having the motif: k-d-k-d-k-(D) 8 -e-e-e-e, wherein each “k” is a constrained ethyl nucleoside, each “e” is a 2′-MOE substituted nucleoside, each “d” is a 2′-deoxynucleoside, and each “D” is a 2′-deoxynucleoside.
10. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable diluent.
11. A method of modulating expression of a target nucleic acid in a cell comprising contacting the cell with the compound of claim 1 .
12. The method of claim 11 , wherein the cell is in an animal.