Compositions and methods for modulating HBV expression
View Patent ↗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 consists of 20 contiguous nucleobases complementary to an equal length portion of nucleobases 1583 to 1602 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 1; 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 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 claim 1 , wherein the modified oligonucleotide comprises the nucleobase sequence of SEQ ID NO: 3, 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, wherein each internucleoside linkage in the gap segment is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.
22. The compound of claim 21 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
23. The compound of claim 21 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.
24. The compound of claim 1 , wherein the compound consists of the formula: