Oligomeric compounds and compositions for the use in modulation of microRNAs
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/04
A61K-031/70
출원번호
US-0161286
(2007-01-27)
등록번호
US-8129515
(2012-03-06)
국제출원번호
PCT/US2007/061186
(2007-01-27)
§371/§102 date
20081119
(20081119)
국제공개번호
WO2007/090073
(2007-08-09)
발명자
/ 주소
Esau, Christine
Swayze, Eric E.
Bhat, Balkrishen
Kinberger, Garth A.
출원인 / 주소
Isis Pharmaceuticals, Inc.
대리인 / 주소
Isis Pharmaceuticals, Inc. Patent Department
인용정보
피인용 횟수 :
29인용 특허 :
127
초록▼
Compounds, compositions and methods are provided for modulating the levels expression, processing and function of miRNAs. The compositions comprise oligomeric compounds targeted to small non-coding RNAs and miRNAs. The oligomeric compounds possess potent miRNA inhibitory activity, and further exhibi
Compounds, compositions and methods are provided for modulating the levels expression, processing and function of miRNAs. The compositions comprise oligomeric compounds targeted to small non-coding RNAs and miRNAs. The oligomeric compounds possess potent miRNA inhibitory activity, and further exhibit improved therapeutic index. Further provided are methods for selectively modulating miRNA activity in a cell.
대표청구항▼
1. An oligomeric compound comprising an oligonucleotide consisting of 17 to 29 nucleosides linked by internucleoside linking groups, said oligonucleotide having an internal region located between two external regions, wherein each external region independently comprises from 1 to 3 nucleosides, each
1. An oligomeric compound comprising an oligonucleotide consisting of 17 to 29 nucleosides linked by internucleoside linking groups, said oligonucleotide having an internal region located between two external regions, wherein each external region independently comprises from 1 to 3 nucleosides, each external region comprises a stabilizing modification, and the internal region comprises at least 10 β-D-2′-deoxy-2′-fluororibofuranosyl nucleosides; and wherein the oligomeric compound comprises a sequence substantially complementary to a microRNA. 2. An oligomeric compound comprising an oligonucleotide having the formula: 5′-T1-(Nu1-L1)n1-(Nu2-L2)n2-Nu2(L3-Nu3)n3-T2-3′ wherein: each Nu1 and Nu3 is, independently, a stabilizing nucleoside;each Nu2 is a β-D-2′-deoxy-2′-fluororibofuranosyl nucleoside;each L1, L2 and L3 is, independently, an internucleoside linking group;each T1 and T2 is, independently, H, a hydroxyl protecting group, an optionally linked conjugate group or a capping group;n1 is from 1 to 3;n2 is from about 14 to about 22; andn3 is from 1 to 3; and wherein the oligomeric compound comprises a sequence substantially complementary to a microRNA. 3. An oligomeric compound comprising an oligonucleotide having the formula I: T1-(Nu1)n1-(Nu2)n2-(Nu3)n3-(Nun4)-(Nu5)n5-T2, wherein:Nu1and Nu5are, independently, 2′ modified nucleosides;Nu2 and Nu4 are β-D-2′-deoxy-2′-fluororibofuranosyl nucleosides;Nu3 is a 2′-modified nucleoside;each of n1 and n5 is, independently, from 1 to 3;the sum of n2 plus n4 is between 10 and 25;n3 is from 0 and 5;each T1 and T2 is, independently, H, a hydroxyl protecting group, an optionally linked conjugate group or a capping group; and wherein the oligomeric compound has a sequence substantially complementary to a microRNA. 4. The oligomeric compound of claim 3, wherein: the sum of n2 and n4 is 16 or 17;n1 is 2;n3 is 2 or 3; andn5 is 2. 5. The oligomeric compound of claim 3, wherein the formula I is selected from: formula I: n1=2, n2=19, n3=0, n4=0, n5=2;formula I: n1=2, n2=2, n3=3, n4=14, n5=2;formula I: n1=2, n2=5, n3=3, n4=11, n5=2;formula I: n1=2, n2=8, n3=3, n4=8, n5=2;formula I: n1=2, n2=11, n3=3, n4=5, n5=2;formula I: n1=2, n2=14, n3=3, n4=2, n5=2;formula I: n1=2, n2=9, n3=3, n=7, n5=2,;formula I: n1=2, n2=10, n3=3, n4=6, n5=2;formula I: n1=2, n2=12, n3=3, n4=4, n5=2;formula I: n1=2, n2 =3, n3=3, n4=13, n5=2;formula I: n1=2, n2=4, n3=3, n4=12, n5=2;formula I: n1=2, n2=6, n3=3, n4=10, n5=2;formula I: n1=2, n2=7, n3=3, n4=9, n5=2;formula I: n1=2, n2=13, n3=3, n4=3, n5=2;formula I: n1=2, n2=8, n3=6, n4=5, n5=2;formula I: n1=2, n2=2, n3=2, n4=15, n5=2;formula I: n1=2, n2=3, n3=2, n4=14, n5=2;formula I: n1=2, n2=4, n3=2, n4=13, n5=2;formula I: n1=2, n2=5, n3=2, n4=12, n5=2;formula I: n1=2, n2=6, n3=2, n4=11, n5=2;formula I: n1=2, n2=7, n3=2, n4=10, n5=2;formula I: n1=2, n2=8, n3=2, n4=9, n5=2;formula I: n1=2, n2=9, n3=2, n4=8, n5=2;formula I: n1=2, n2=10, n3=2, n4=7, n5=2;formula I: n1=2, n2=11, n3=2, n4=6, n5=2;formula I: n1=2, n2=12, n3=2, n4=5, n5=2;formula I: n1=2, n2=13, n3=2, n4=4, n5=2;formula I: n5=2, n2=14, n3=2, n4=3, n5=2; orformula I: n1=2, n2=15, n3=2, n4=2, n5=2. 6. The oligomeric compound of claim 3 wherein each of the 2′-modified nucleosides independently comprises a 2′-substituent group selected from O—C1-C12 alkyl, substituted O—C1-C12 alkyl, O—C2-C12 alkenyl, substituted O—C2-C12 alkenyl, O—C2-C12 alkynyl, substituted O—C2-C12 alkynyl, amino, substituted amino, amide, substituted amide, aralkyl, substituted aralkyl, O-aralkyl, substituted O-aralkyl, N3, SH, CN, OCN, CF3, OCF3, SOCH3, —SO2CH3, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino and polyalkylamino; and wherein each substituent group is, independently, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, O—C1-C12 alkyl, substituted O—C1-C12 alkyl, S—C1-C12 alkyl, substituted S—C1-C12 alkyl, acyl (C(═O)—H), substituted acyl, amino, substituted amino, amide, substituted amide, C1-C12 alkylamino, substituted C1-C 12 alkylamino, C1-C12 aminoalkoxy, substituted C1-C12 aminoalkoxy, C1-C12 alkylaminooxy, substituted C1-C12 alkylaminooxy, guanidinyl, substituted guanidinyl or a protecting group. 7. The oligomeric compound of claim 6 wherein each 2′-substituent group is, independently, OCH3 or O—(CH2)2—OCH3. 8. The oligomeric compound of claim 7 wherein each 2′-substituent group is O—(CH2)2—OCH3. 9. The oligomeric compound of claim 3, wherein the 2′-modified nucleoside is a bicyclic sugar modified nucleoside. 10. The oligomeric compound of claim 9 wherein each of the bicyclic sugar modified nucleosides independently comprises a bridge group between the 2′ and the 4′-carbon atoms comprising from 1 to 8 linked biradical groups independently selected from —O—, —S—, —N(R1)—, —C(R1)(R2)—, —C(R1)═C(R1)—, —C(R1)═N—, —C(═NR1)—, —Si(R1)(R2)—, —S(═O)2—, —S(═O)—, —C(═O)—and —C(═S)—; each R1 and R2 is, independently, H, hydroxyl, C1-C 12 alkyl, substituted C1-C 12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, a heterocycle radical, a substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, substituted oxy (—O—), amino, substituted amino, azido, carboxyl, substituted carboxyl, acyl, substituted acyl, CN, thiol, substituted thiol, sulfonyl (S(═O)2—H), substituted sulfonyl, sulfoxyl (S(═O)—H) or substituted sulfoxyl; andwherein each substituted group comprises a substituent group, independently selected from among, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, amino, substituted amino, acyl, substituted acyl, C1-C12 aminoalkyl, C1-C12 aminoalkoxy, substituted C1-C12 aminoalkyl, substituted C1-C12 aminoalkoxy and a protecting group. 11. The oligomeric compound of claim 10 wherein each bicyclic sugar modified nucleoside independently comprises from 1 to 4 of the linked biradical groups. 12. The oligomeric compound of claim 10 wherein each bridge group is, independently, —CH2—, —(CH2)2—, —CH2—O—, —(CH2)2—O—or —CH2—N(R3)—O— wherein R3 is H or C1-C12 alkyl. 13. The oligomeric compound of claim 10 wherein each bridge group is, independently, —CH2—O—or —(CH2)2—O—. 14. The oligomeric compound of claim 3, wherein Nu1 is a 2′-modified nucleoside comprising a 2′—O—(CH2)2—OCH3, Nu3 is a 2′-modified nucleoside comprising a 2′-O—(CH2)2—OCH3, Nu5 is a 2′-modified nucleoside comprising a 2′—O—(CH2)2—OCH3, T1 is H and T2 is H, and wherein formula I is selected from: formula I: n1=2, n2=19, n3=0, n4=0, n5=2;formula I: n1=2, n2=2, n3=3, n4=14, n5=2;formula I: n1=2, n2=5, n3=3, n4=11, n5=2;formula I: n1=2, n2=8, n3=3, n4=8, n5=2;formula I: n1=2, n2=11, n3=3, n4=5, n5=2;formula I: n1=2, n2=14, n3=3, n4=2, n5=2;formula I: n1=2, n2=9, n3=3, n4=7, n5=2;formula I: n1=2, n2=10, n3=3, n4=6, n5=2;formula I: n1=2, n2=12, n3=3, n4=4, n5=2;formula I: n1=2, n2=3, n3=3, n4=13, n5=2;formula I: n1=2, n2=4, n3=3, n4=12, n5=2;formula I: n1=2, n2=6, n3=3, n4=10, n5=2;formula I: n1=2, n2=7, n3=3, n4=9, n5=2;formula I: n1=2, n2=13, n3=3, n4=3, n5=2;formula I: n1=2, n2=8, n3=6, n4=5, n5=2;formula I: n1=2, n2=2, n3=2, n4=15, n5=2;formula I: n1=2, n2=3, n3=2, n4=14, n5=2;formula I: n1=2, n2=4, n3=2, n4=13, n5=2;formula I: n1=2, n2=5, n3=2, n4=12, n5=2;formula I: n1=2, n2=6, n3=2, n4=11, n5=2;formula I: n1=2, n2=7, n3=2, n4=10, n5=2;formula I: n1=2, n2=8, n3=2, n4=9, n5=2;formula I: n1=2, n2=9, n3=2, n4=8, n5=2;formula I: n1=2, n2=10, n3=2, n4=7, n5=2;formula I: n1=2, n2=11, n3=2, n4=6, n5=2;formula I: n1=2, n2=12, n3=2, n4=5, n5=2;formula I: n1=2, n2=13, n3=2, n4=4, n5=2;formula I: n5=2, n2=14, n3=2, n4=3, n5=2; orformula I: n1=2, n2=15, n3=2, n4=2, n5=2. 15. The oligomeric compound of any of claim 3, 5, or 14 wherein the oligomeric compound comprises at least one phosphorothioate internucleoside linkage. 16. The oligomeric compound of any of claim 3, 5, or 14 wherein each internucleoside linkage comprises a phosphorothioate internucleoside linkage. 17. The oligomeric compound of claim 3 wherein T1 is H and T2 is H. 18. The oligomeric compound of claim 3 comprising a sequence selected from SEQ ID NOs 1 to 470. 19. A method of inhibiting miRNA activity, comprising contacting a cell with an oligomeric compound of claim 3. 20. A method of inhibiting miRNA activity, comprising contacting a cell with an oligomeric compound of claim 1, wherein the oligomeric compound comprises a sequence selected from SEQ ID NOs 1 to 470. 21. A method of inhibiting miRNA activity, comprising contacting a cell with an oligomeric compound of claim 2, wherein the oligomeric compound comprises a sequence selected from SEQ ID NOs 1 to 470. 22. A method of inhibiting miRNA activity, comprising contacting a cell with an oligomeric compound of claim 3, wherein the oligomeric compound comprises a sequence selected from SEQ ID NOs 1 to 470. 23. The method of claim 22 wherein the cell is in vitro. 24. The method of claim 22 wherein the cell is in vivo. 25. A method of inhibiting miRNA activity in vivo, comprising contacting an animal with the oligomeric compound of claim 1, 2, or 3, wherein the oligomeric compound comprises a sequence selected from SEQ ID NOs 1 to 470, thereby inhibiting miRNA activity. 26. A method of inhibiting miR-122 activity, comprising contacting an animal with the oligomeric compound of claim 14, wherein the oligomeric compound comprises the nucleobase sequence of SEQ ID NO: 19. 27. The method of claim 26, further comprising decreasing cholesterol levels.
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