IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0416100
(2017-01-26)
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등록번호 |
US-10093924
(2018-10-09)
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발명자
/ 주소 |
- Uhlmann, Eugen
- Weber, Markus
- Subramanian, Romesh
- Rockel, Thomas Dino
- Krieg, Arthur M.
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출원인 / 주소 |
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대리인 / 주소 |
Wolf, Greenfield & Sacks, P.C.
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인용정보 |
피인용 횟수 :
0 인용 특허 :
49 |
초록
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The disclosure provides multimeric oligonucleotide compounds, comprising two or more target-specific oligonucleotides (e.g., antisense oligonucleotides (ASOs)), each being resistant to cleavage, and linked together by a cleavable linker. In particular, two or more linked target-specific oligonucleot
The disclosure provides multimeric oligonucleotide compounds, comprising two or more target-specific oligonucleotides (e.g., antisense oligonucleotides (ASOs)), each being resistant to cleavage, and linked together by a cleavable linker. In particular, two or more linked target-specific oligonucleotides, each to a different target, allows concomitant inhibition of multiple genes' expression levels, while exhibiting favorable pharmacokinetic and pharmacodynamic properties. Methods of making and uses of the described compounds are also provided.
대표청구항
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1. A single-stranded nucleic acid compound comprising the general formula: 5′X3′-L-5′X3′, wherein each X is independently a single-stranded targeting oligonucleotide of 8 to 16 nucleotides in length having a region of complementarity comprising at least 7 contiguous nucleotides complementary to a ta
1. A single-stranded nucleic acid compound comprising the general formula: 5′X3′-L-5′X3′, wherein each X is independently a single-stranded targeting oligonucleotide of 8 to 16 nucleotides in length having a region of complementarity comprising at least 7 contiguous nucleotides complementary to a target region of an mRNA, wherein adjacent nucleotides of the region of complementarity of each X comprise phosphorothioate linkages, andwherein L is a linker consisting of 1 to 10 pyrimidine nucleotides linked through phosphodiester linkages that links at least two Xs and that is i) more susceptible to cleavage in a liver mammalian extract than each X and ii) more susceptible to cleavage in liver mammalian extract than mammalian serum or plasma, andwherein when the target regions complementary to the first X and second X do not overlap in the mRNA, the 5′-end of the target region complementary to the first X and the 3′-end of the target region complementary to the second X are not within a distance of 0 to 4 nucleotides in the mRNA. 2. The single-stranded nucleic acid compound of claim 1, wherein the pyrimidine nucleotides are thymidines or uridines. 3. A composition comprising a single-stranded nucleic acid compound of claim 1 and a carrier. 4. A composition comprising a single-stranded nucleic acid compound of claim 1 in a buffered solution. 5. A pharmaceutical composition comprising a single-stranded nucleic acid compound of claim 1 and a pharmaceutically acceptable carrier. 6. A kit comprising a container housing the composition of claim 3. 7. The single-stranded nucleic acid compound of claim 2, wherein the pyrimidine nucleotides are thymidines. 8. The single-stranded nucleic acid compound of claim 2, wherein the pyrimidine nucleotides are uridines. 9. The single-stranded nucleic acid compound of claim 1, wherein each targeting oligonucleotide comprises phosphorothioate internucleotide linkages between all nucleotides. 10. The single-stranded nucleic acid compound of claim 1, wherein each targeting oligonucleotide comprises a locked nucleic acid (LNA) nucleotide, ethylene bridged nucleic acid (ENA) nucleotide, 2′-O-methyl nucleotide, or 2′-fluoro-deoxyribonucleotide. 11. A method of delivering multiple targeting oligonucleotides to a cell, the method comprising: contacting a cell with a single-stranded nucleic acid compound of claim 1 under conditions in which the compound enters into the cell. 12. The method of claim 11, wherein the cell is in vitro. 13. The method of claim 11, wherein the cell is in vivo. 14. The method of claim 11, wherein the single-stranded nucleic acid compound is delivered systemically to a subject comprising the cell. 15. The single-stranded nucleic acid compound of claim 1, wherein the linker consists of 2 to 4 pyrimidine nucleotides linked through phosphodiester linkages. 16. A compound comprising the general formula: 5′X3′-L-5′X3′, wherein each X is independently a single-stranded targeting oligonucleotide of 8 to 16 nucleotides in length having a region of complementarity comprising at least 7 contiguous nucleotides complementary to a target region of an mRNA, wherein adjacent nucleotides of the region of complementarity of each X comprise phosphorothioate linkages,wherein L is a linker consisting of 1 to 10 pyrimidine nucleotides linked through phosphodiester linkages that links the Xs and that is i) more susceptible to cleavage in a liver mammalian extract than each X and ii) more susceptible to cleavage in liver mammalian extract than in mammalian serum or plasma,wherein when the target regions complementary to the first X and second X do not overlap in the mRNA, the 5′-end of the target region complementary to the first X and the 3′-end of the target region complementary to the second X are not within a distance of 0 to 4 nucleotides in the mRNA, andwherein the compound does not mediate degradation of the target nucleic acids by an RNAi pathway. 17. The compound of claim 16, wherein the pyrimidine nucleotides are thymidines or uridines. 18. The compound of claim 17, wherein the pyrimidine nucleotides are thymidines. 19. The compound of claim 17, wherein the pyrimidine nucleotides are uridines. 20. The compound of claim 16, wherein each targeting oligonucleotide comprises phosphorothioate internucleotide linkages between all nucleotides. 21. The compound of claim 16, wherein each targeting oligonucleotide comprises a locked nucleic acid (LNA) nucleotide, ethylene bridged nucleic acid (ENA) nucleotide, 2′-O-methyl nucleotide, or 2′-fluoro-deoxyribonucleotide. 22. The compound of claim 16, wherein the linker consists of 2 to 4 pyrimidine nucleotides linked through phosphodiester linkages.
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