IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0698239
(2015-04-28)
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등록번호 |
US-9732340
(2017-08-15)
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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 :
1 인용 특허 :
45 |
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 compound comprising the general formula: X-L-[X-L]i-X, wherein i is an integer from 0 to 9, the value of which indicates the number of units of [X-L]i present in the compound;wherein each X is independently a single stranded targeting oligonucleotide of 8 to 16 nucleotides in length having a re
1. A compound comprising the general formula: X-L-[X-L]i-X, wherein i is an integer from 0 to 9, the value of which indicates the number of units of [X-L]i present in the compound;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 a genomic target sequence, wherein each targeting oligonucleotide is complementary to an mRNA that encodes a protein having an activity in liver or kidney, and wherein adjacent nucleotides of the region of complementarity of each X comprise phosphorothioate linkages, and each L is an single stranded oligonucleotide linker consisting of 2 to 4 contiguous thymidine or uridine nucleotide residues linked through phosphodiester linkages that links at least two Xs and that is more susceptible to cleavage in a mammalian liver or kidney cell extract than each X;wherein when i=0, and the general formula is 5′X3′-L-5′X3′ and when the target regions complementary to the first X and second X do not overlap in the genomic target sequence, 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 genomic target sequence;wherein at least one L does not comprise an oligonucleotide having a self-complementary nucleotide sequence; andwherein at least one L does not comprise an oligonucleotide having a nucleotide sequence that is complementary to a region of the genomic target sequence that is contiguous with the target regions complementary to two immediately flanking Xs. 2. The compound of claim 1, wherein i is an integer from 1 to 9. 3. The compound of claim 1, wherein each L consists of 3 or 4 contiguous thymidine or uridine nucleotide residues linked through phosphodiester linkages. 4. The compound of claim 1, wherein each L consists of 4 contiguous thymidine or uridine nucleotide residues linked through phosphodiester internucleotide linkages. 5. The compound of claim 1, wherein i is 0. 6. The compound of claim 1, wherein each X of the compound has a different region of complementarity than each other X of the compound, such that the Xs of the compound target different genomic target sequences. 7. The compound of claim 5, wherein L consists of 3 or 4 contiguous thymidine or uridine nucleotide residues linked through phosphodiester linkages. 8. The compound of claim 5, wherein L consists of 4 contiguous thymidine or uridine nucleotide residues linked through phosphodiester linkages. 9. The compound of claim 3, wherein each L consists of 3 or 4 contiguous thymidine nucleotide residues linked through phosphodiester linkages. 10. The compound of claim 4, wherein each L consists of 4 contiguous thymidine nucleotide residues linked through phosphodiester linkages. 11. The compound of claim 10, wherein each targeting oligonucleotide is complementary with an mRNA that encodes a protein having an activity in liver. 12. The compound of claim 3, wherein each L consists of 3 or 4 contiguous uridine nucleotide residues linked through phosphodiester linkages. 13. The compound of claim 4, wherein each L consists of 4 contiguous uridine nucleotide residues linked through phosphodiester linkages. 14. The compound of claim 7, wherein each L consists of 3 or 4 contiguous thymidine nucleotide residues linked through phosphodiester linkages. 15. The compound of claim 8, wherein each L consists of 4 contiguous thymidine nucleotide residues linked through phosphodiester linkages. 16. The compound of claim 15, wherein each targeting oligonucleotide is complementary to an mRNA that encodes a protein having an activity in liver. 17. The compound of claim 7, wherein each L consists of 3 or 4 contiguous uridine nucleotide residues linked through phosphodiester linkages. 18. The compound of claim 8, wherein each L consists of 4 contiguous uridine nucleotide residues linked through phosphodiester linkages.
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