IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
|
출원번호 |
US-0742652
(2008-11-13)
|
등록번호 |
US-8637478
(2014-01-28)
|
국제출원번호 |
PCT/US2008/083448
(2008-11-13)
|
§371/§102 date |
20101008
(20101008)
|
국제공개번호 |
WO2009/064920
(2009-05-22)
|
발명자
/ 주소 |
|
출원인 / 주소 |
- Isis Pharmaceuticals, Inc.
|
대리인 / 주소 |
Isis Pharmaceuticals, Inc Patent Dept.
|
인용정보 |
피인용 횟수 :
5 인용 특허 :
20 |
초록
The present invention provides compounds and methods for modulating expression of a protein, including, but not limited to, modulating splicing of a pre-mRNA to modulate the amount of one or more variants of a protein.
대표청구항
▼
1. A method of modulating expression of a target protein in a cell by altering splicing of a target pre-mRNA encoding the target protein comprising contacting the cell with an oligomeric compound comprising a contiguous sequence of nucleosides having the formula I: T1-(Nu1)n1-(Nu2)n2-(Nu3)n3-(Nu4)n4
1. A method of modulating expression of a target protein in a cell by altering splicing of a target pre-mRNA encoding the target protein comprising contacting the cell with an oligomeric compound comprising a contiguous sequence of nucleosides having the formula I: T1-(Nu1)n1-(Nu2)n2-(Nu3)n3-(Nu4)n4-(Nu5)n5-T2, wherein:Nu1 and Nu5 are, independently, 2′ stabilizing 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 0 to 3;the sum of n2 plus n4 is between 10 and 25;n3 is from 0 to 5; andeach T1 and T2 is, independently, H, a hydroxyl protecting group, an optionally linked conjugate group or a capping group;wherein the oligomeric compound has a nucleobase sequence complementary to the target pre-mRNA; and thereby altering splicing of the pre-mRNA and thereby modulating expression of the target protein. 2. The method of claim 1, wherein, Nu1 and Nu5 are, independently, 2% modified nucleosides. 3. The method of claim 2, wherein, each of the 2′-modified nucleosides independently comprises a 2′-substituent group selected from halogen, 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-C12 alkylamino, C1-C12 aminoalkoxy, substituted C1-C12 aminoalkoxy, C1-C12 alkylaminooxy, substituted C1-C12 alkylaminooxy, guanidinyl, substituted guanidinyl or a protecting group. 4. The method of claim 3, wherein, each 2′-substituent group is, independently, halogen, O(CH2)0-2CH3, O(CH2)2OCH3, O(CH2)2SCH3, OCH2C(H)CH2, O(CH2)2ON(CH3)2 or OCH2C(═O)N(H)CH3. 5. The method of claim 4, wherein, each 2′-substituent group is, independently, OCH3 or O—(CH2)2—OCH3. 6. The method of claim 5, wherein, each 2′-substituent group is O—(CH2)2—OCH3. 7. The method of claim 2, wherein, the 2′-modified nucleoside is a bicyclic sugar modified nucleoside. 8. The method of claim 4, 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-C12 alkyl, substituted C1-C12 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 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, amino, substituted amino, acyl, substituted acyl, C1-C12 aminoalkyl, C1-C12 aminoalkoxy, substituted C1-C12 aminoalkyl, substituted C1-C12 aminoalkoxy or a protecting group. 9. The method of claim 8, wherein, each bicyclic sugar modified nucleoside independently comprises 2 or 3 of the linked biradical groups. 10. The method of claim 9, wherein, each bicyclic sugar modified nucleoside comprises 2 of the linked biradical groups. 11. The method of claim 8, 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. 12. The method of claim 11, wherein, each bridge group is, independently, —CH2—O— or —(CH2)2—O—. 13. The method of claim 1 wherein the oligomeric compound comprises at least one phosphorothioate internucleoside linkage. 14. The method of claim 1 wherein each internucleoside linkage comprises a phosphorothioate internucleoside linkage. 15. The method of claim 1, wherein the target protein is selected from SMN2, Bcl-x, MyD88, Lamin-A, and TNF. 16. The method of any of claim 1, wherein the cell is in an animal. 17. The method of claim 16, wherein the animal is a human.
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