Compositions and methods for modulating angiopoietin-like 3 expression
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/02
C07H-021/04
C12N-015/113
출원번호
US-0701999
(2015-05-01)
등록번호
US-9382540
(2016-07-05)
발명자
/ 주소
Prakash, Thazha P.
Seth, Punit P.
Swayze, Eric E.
Freier, Susan M.
Graham, Mark J.
Crooke, Rosanne M.
출원인 / 주소
Isis Pharmaceuticals, Inc
대리인 / 주소
Ionis Patent Department
인용정보
피인용 횟수 :
2인용 특허 :
119
초록▼
Provided herein are methods, compounds, and compositions for reducing expression of an ANGPTL3 mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for reducing lipids and/or glucose in an animal. Such methods, compounds, and compositions are useful to treat,
Provided herein are methods, compounds, and compositions for reducing expression of an ANGPTL3 mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for reducing lipids and/or glucose in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate any one or more of cardiovascular disease and/or metabolic disease, or a symptom thereof, in an individual in need thereof.
대표청구항▼
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 1140 to 1159 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide
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 1140 to 1159 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% 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′-(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 the modified oligonucleotide comprises at least one 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 2 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: 77, 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 the internucleoside linkages are phosphorothioate linkages between nucleosides 1-2, nucleosides 6-16 and nucleosides 18-20 of the modified oligonucleotide, wherein nucleosides 1-20 are positioned 5′ to 3′. 24. The compound of claim 21, wherein the 2nd, 3rd, 4th and 5th internucleoside linkage from the 5′-end is a phosphodiester internucleoside linkage, wherein the 3rd and 4th internucleoside linkage from the 3′-end is a phosphodiester internucleoside linkage, and wherein each remaining internucleoside linkage is a phosphorothioate internucleoside linkage. 25. The compound of claim 1, having the formula: wherein either R1 is —OCH2CH2OCH3 (MOE) and R2 is H; or R1 and R2 together form a bridge, wherein R1 is —O— and R2 is —CH2—, —CH(CH3)—, or —CH2CH2—, and R1 and R2 are directly connected such that the resulting bridge is selected from: —O—CH2—, —O—CH(CH3)—, and —O—CH2CH2—;and for each pair of R3 and R4 on the same ring, independently for each ring: either R3 is selected from H and —OCH2CH2OCH3 and R4 is H; or R3 and R4 together form a bridge, wherein R3 is —O—, and R4 is —CH2—, —CH(CH3)—, or —CH2CH2— and R3 and R4 are directly connected such that the resulting bridge is selected from: —O—CH2—, —O—CH(CH3)—, and —O—CH2CH2—;and R5 is selected from H and —CH3;and Z is selected from S− and O−. 26. The compound of claim 1, having the formula: 27. A composition comprising the compound of claim 1, or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 28. A composition comprising the compound of claim 26, or a salt thereof, and a pharmaceutically acceptable carrier or diluent.
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이 특허에 인용된 특허 (119)
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