[미국특허]
Compositions and methods for modulating HBV expression
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-015/113
C07H-021/04
C12N-015/11
A61K-031/7088
A61K-031/713
출원번호
US-0822493
(2015-08-10)
등록번호
US-9932580
(2018-04-03)
발명자
/ 주소
Prakash, Thazha P.
Seth, Punit P.
Swayze, Eric E.
출원인 / 주소
Ionis Pharmaceuticals, Inc.
대리인 / 주소
Knobbe, Martens, Olson & Bear, LLP
인용정보
피인용 횟수 :
0인용 특허 :
218
초록
Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.
대표청구항▼
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,
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′-(CH2)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; anda 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; anda 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; anda 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; anda 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.
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