Therapeutic compositions
This application relates to therapeutic siRNA agents and methods of making and using the agents.
1. An RNA agent comprising: a sense sequence having 4-12 asymmetrical 2′-O-alkyl modifications, at least 4 of which occur within the 6 terminal nucleotides of the 5′ end; and an antisense sequence having at least 4 asymmetrical phosphorothioate modifications, wherein the RNA agent comprises a multivalent galactose or a multivalent N-acetyl-galactosamine, and wherein the antisense sequence targets a human gene sequence.
2. The RNA agent of claim 1 , wherein the RNA agent is at least 21 nucleotides in length, and the duplex region of the RNA agent is about 19 nucleotides in length.
3. The RNA agent of claim 1 , wherein the RNA agent has a duplex region of about 19 nucleotides in length and one or two 3′ overhangs of about 2 nucleotides in length.
4. The RNA agent of claim 1 , wherein the antisense sequence contains 4-20 asymmetrical phosphorothioate modifications.
5. The RNA agent of claim 1 , wherein each of the 2′-O-alkyl modifications are 2′-O-methyl modifications.
6. The RNA agent of claim 1 , wherein the antisense strand further comprises at least one asymmetric modification selected from the group consisting of 2′-5′-linkages, L sugars, modified sugars, nucleobasc modifications, cation groups, Zwitterionic groups, and conjugate groups.
7. The RNA agent of claim 1 , wherein the sense strand has 4 asymmetrical 2′-O-alkyl modifications within the 6 terminal nucleotides of the 5′ end, and at least one 2′-O-alkyl modification in another portion of the sense strand.
8. The RNA agent of claim 7 , wherein antisense strand does not contain any 2′-O-alkyl modifications, and the sense strand does not contain any phosphorothioate modifications.
9. An RNA agent comprising: a sense sequence having 4-12 asymmetrical 2′-O-alkyl modifications, at least 4 of which occur within the 6 terminal nucleotides of the 3′ end; and an antisense sequence having at least 4 asymmetrical phosphorothioate modifications, wherein the RNA agent comprises a multivalent galactose or a multivalent N-acetyl-galactosamine, and wherein the antisense sequence targets a human gene sequence.
10. The RNA agent of claim 9 , wherein the RNA agent is at least 21 nucleotides in length, and the duplex region of the RNA agent is about 19 nucleotides in length.
11. The RNA agent of claim 9 , wherein the RNA agent has a duplex region of about 19 nucleotides in length and one or two 3′ overhangs of about 2 nucleotides in length.
12. The RNA agent of claim 9 , wherein the antisense sequence contains 4-20 asymmetrical phosphorothioate modifications.
13. The RNA agent of claim 9 , wherein each of the 2′-O-alkyl modifications are 2′-O-methyl modifications.
14. The RNA agent of claim 9 , wherein the antisense strand further comprises at least one asymmetric modification selected from the group consisting of 2′-5′-linkages, L sugars, modified sugars, nucleobase modifications, cation groups, Zwitterionic groups, and conjugate groups.
15. The RNA agent of claim 9 , wherein the sense strand has 4 asymmetrical 2′-O-alkyl modifications within the 6 terminal nucleotides of the 3′ end, and at least one 2′-O-alkyl modification in another portion of the sense strand.
16. The RNA agent of claim 15 , wherein antisense strand does not contain any 2′-O-alkyl modifications, and the sense strand does not contain any phosphorothioate modifications.
17. The RNA agent of claim 1 , wherein the sense strand further comprises at least one asymmetric modification selected from the group consisting of 2′-5′-linkages, L sugars, modified sugars, nucleobase modifications, cation groups, Zwitterionic groups, and conjugate groups.
18. The RNA agent of claim 9 , wherein the sense strand further comprises at least one asymmetric modification selected from the group consisting of 2′-5′-linkages, L sugars, modified sugars, nucleobase modifications, cation groups, Zwitterionic groups, and conjugate groups.