Compositions and methods for modulating HBV expression
Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.
1. A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide has a nucleobase sequence consisting of any one of the nucleobase sequences of SEQ ID NOs: 4, 5, 6, 7, 8, 9, or 11, and wherein the conjugate group comprises:
2. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar.
3. The compound of claim 2 , wherein at least one modified sugar is a bicyclic sugar.
4. The compound of claim 2 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl, a 3′-fluoro-HNA or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2.
5. The compound of claim 2 , wherein at least one modified sugar is 2′-O-methoxyethyl.
6. The compound of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.
7. The compound of claim 6 , wherein the modified nucleobase is a 5-methylcytosine.
8. The compound of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide.
9. The compound of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide.
10. The compound of claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.
11. The compound of claim 10 , wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages.
12. The compound of claim 10 , wherein the modified oligonucleotide comprises at least two phosphorothioate internucleoside linkages.
13. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded.
14. The compound of claim 1 , wherein the modified oligonucleotide is double stranded.
15. The compound of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
16. The compound of claim 15 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.
17. The compound of claim 16 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
18. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded and consists of 20 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 4, and wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, and wherein each cytosine residue is a 5-methylcytosine.
19. The compound of claim 18 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.
20. The compound of claim 19 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
21. The compound of claims 20 , wherein the modified oligonucleotide further comprises at least 2 phosphodiester internucleoside linkages.
22. The compound of claim 18 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.
23. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded and consists of 20 linked nucleosides having a nucleobase sequence consisting of any of SEQ ID NOs: 7, 6, or 8, and wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 6 linked nucleosides; and
a 3′ wing segment consisting of 4 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, and wherein each cytosine residue is a 5-methylcytosine.
24. The compound of claim 23 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.
25. The compound of claim 24 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
26. The compound of claims 25 , wherein the modified oligonucleotide further comprises at least 2 phosphodiester internucleoside linkages.
27. The compound of claim 23 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.
28. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded and consists of 17 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 5, and wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 3 linked nucleosides; and
a 3′ wing segment consisting of 4 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, and wherein each cytosine residue is a 5-methylcytosine.
29. The compound of claim 28 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.
30. The compound of claim 29 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
31. The compound of claims 30 , wherein the modified oligonucleotide further comprises at least 2 phosphodiester internucleoside linkages.
32. The compound of claim 28 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.
33. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded and consists of 16 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 9, and wherein the modified oligonucleotide comprises:
a gap segment consisting of 10 linked deoxynucleosides;
a 5′ wing segment consisting of 3 linked nucleosides; and
a 3′ wing segment consisting of 3 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein the 3 linked nucleosides of the 5′ wing segment comprise a 2′-O-methoxyethyl sugar, a constrained ethyl sugar, and a constrained ethyl sugar in the 5′ to 3′ direction; wherein the 3 linked nucleosides of the 3′ wing segment comprise a constrained ethyl sugar, a constrained ethyl sugar, and a 2′-O-methoxyethyl sugar in the 5′ to 3′ direction; and wherein each cytosine residue is a 5-methylcytosine.
34. The compound of claim 33 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.
35. The compound of claim 34 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
36. The compound of claims 35 , wherein the modified oligonucleotide further comprises at least 2 phosphodiester internucleoside linkages.
37. The compound of claim 33 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.
38. The compound of claim 1 , wherein the modified oligonucleotide is single-stranded and consists of 18 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 11, and wherein the modified oligonucleotide comprises:
a gap segment consisting of 8 linked deoxynucleosides;
a 5′ wing segment consisting of 5 linked nucleosides; and
a 3′ wing segment consisting of 5 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein the 5 linked nucleosides of the 5′ wing segment comprise a constrained ethyl sugar, a deoxy sugar, a constrained ethyl sugar, a deoxy sugar, and a constrained ethyl sugar in the 5′ to 3′ direction; wherein each of the 5 linked nucleosides of the 3′ wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each cytosine residue is a 5-methylcytosine.
39. The compound of claim 38 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.
40. The compound of claim 39 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
41. The compound of claims 40 , wherein the modified oligonucleotide further comprises at least 2 phosphodiester internucleoside linkages.
42. The compound of claim 38 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.