Compositions and methods for optimizing cleavage of RNA by RNase H
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-015/85
C07H-021/02
C07H-021/04
출원번호
US-0592919
(2005-03-15)
등록번호
US-8790919
(2014-07-29)
국제출원번호
PCT/US2005/008428
(2005-03-15)
§371/§102 date
20070731
(20070731)
국제공개번호
WO2005/089268
(2005-09-29)
발명자
/ 주소
Migawa, Michael T.
Lima, Walter F.
Swayze, Eric E.
Nichols, Joshua
Wu, Hongjiang
Prakash, Thazha P.
Wyrzykiewicz, Tadeusz Krzysztof
Bhat, Balkrishen
Crooke, Stanley T.
출원인 / 주소
Isis Pharmaceuticals, Inc.
대리인 / 주소
Isis Pharmaceutical, Inc. Patent Dept.
인용정보
피인용 횟수 :
1인용 특허 :
12
초록▼
The present invention provides compositions and methods for the optimization of cleavage of RNA species by RNase H. In some embodiments, the invention provides oligonucleotides that possess two or more regions of differing conformation, and at least one transitional nucleobase positioned between the
The present invention provides compositions and methods for the optimization of cleavage of RNA species by RNase H. In some embodiments, the invention provides oligonucleotides that possess two or more regions of differing conformation, and at least one transitional nucleobase positioned between the regions that is capable of modulating transfer of the helical conformation characteristic of the region bound to the 3′hydroxy thereof, to the region bound to the 5′ hydroxyl thereof.
대표청구항▼
1. A method of modulating the expression of a target RNA molecule in a eukaryotic cell comprising the step of contacting the cell with an oligonucleotide consisting of 8 to 80 linked nucleosides and having a) a first region of nucleotides, each having a first conformation which, when the oligonucleo
1. A method of modulating the expression of a target RNA molecule in a eukaryotic cell comprising the step of contacting the cell with an oligonucleotide consisting of 8 to 80 linked nucleosides and having a) a first region of nucleotides, each having a first conformation which, when the oligonucleotide is bound to the target RNA molecule, forms a substrate for cleavage by an RNase;b) a second region of nucleotides, each having a second conformation which, when the oligonucleotide is bound to the target RNA molecule does not form a substrate for cleavage by an RNase, andc) a transition moiety positioned between the first and the second regions which modulates the transmission of the conformation of the second region into the first region, wherein the transition moiety comprises at least one modified nucleotide that does not form hydrogen bonds with the target RNA molecule, wherein the modified nucleotide is (i) a modified or unmodified sugar abasic nucleotide, or (ii) comprises a modified nucleobase selected from the group consisting of a universal base, a hydrophobic base, and a fluorinated nucleobase. 2. The method of claim 1, wherein the second region is positioned 5′ to the first region. 3. The method of claim 1, wherein the first region comprises deoxynucleotides. 4. The method of claims 3, wherein the second region comprises 2′-O-alkoxyalkyl ribonucleotides. 5. The method of claim 4, wherein the 2′-O-alkoxyalkyl ribonucleotides are 2′-O-methoxyethyl ribonucleotides. 6. The method of claim 1, wherein the internucleotide linkages in the first or second regions are phosphorothioates. 7. The method of claim 1, wherein the modified nucleobase of the transition moiety is capable of π stacking with adjacent bases. 8. The method of claim 7, wherein the modified base moiety is tetrafluoroindolyl. 9. The method of claim 1, wherein the modified sugar nucleotide is a 2′-ara-modified nucleotide. 10. The method of claim 9, wherein the 2′-ara-modified nucleotide is a 2′-ara-fluoro nucleotide. 11. The method of claim 1, wherein the oligonucleotide comprises a third region of nucleotides, each having a conformation which, when the oligonucleotide is bound to the target RNA molecule does not form a substrate for cleavage by an RNase. 12. The method of claim 11, wherein the third region has the same conformation as the second region. 13. The method of claims 12, wherein the second region comprises 2′-O-alkoxyalkyl ribonucleotides. 14. The method of claim 13, wherein the 2′-O-alkoxyalkyl ribonucleotides are 2′-O-methoxyethyl ribonucleotides. 15. The method of claim 11, wherein the oligonucleotide comprises a second transition moiety which modulates the transmission of the conformation of the third region into the first region, and wherein the second transition moiety comprises at least one modified nucleotide that does not form hydrogen bonds with the target RNA molecule, wherein the modified nucleotide is (i) a modified or unmodified sugar abasic nucleotide, or (ii) comprises a modified nucleobase selected from the group consisting of a universal base, a hydrophobic base, and a fluorinated nucleobase. 16. The method of claim 15, wherein the modified base nucleotide of the second transition moiety comprises a modified base moiety capable of π stacking with adjacent bases. 17. The method of claim 15, wherein the modified base moiety of the second transition moiety is tetrafluoroindolyl. 18. The method of claim 15, wherein the modified sugar nucleotide of the second transition moiety is a 2′-ara-modified nucleotide. 19. The method of claim 15, wherein the 2′-ara-modified nucleotide of the second transition moiety is a 2′-ara-fluoro nucleotide. 20. The method of claim 15, wherein the modified sugar moiety of the second transition moiety is an acyclic sugar analog. 21. The method of claim 1, wherein the eukaryotic cell is in an animal.
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이 특허에 인용된 특허 (12)
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