IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0745429
(2007-05-07)
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등록번호 |
US-9045754
(2015-06-02)
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발명자
/ 주소 |
- Bhanot, Sanjay
- Geary, Richard S.
- McKay, Robert
- Monia, Brett P.
- Seth, Punit P.
- Siwkowski, Andrew M.
- Swayze, Eric E.
- Wancewicz, Edward
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출원인 / 주소 |
- Isis Pharmaceuticals, Inc.
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대리인 / 주소 |
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인용정보 |
피인용 횟수 :
1 인용 특허 :
171 |
초록
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The present disclosure describes short antisense compounds, including such compounds comprising chemically-modified high-affinity monomers 8-16 monomers in length. Certain such short antisense compound are useful for the reduction of target nucleic acids and/or proteins in cells, tissues, and animal
The present disclosure describes short antisense compounds, including such compounds comprising chemically-modified high-affinity monomers 8-16 monomers in length. Certain such short antisense compound are useful for the reduction of target nucleic acids and/or proteins in cells, tissues, and animals with increased potency and improved therapeutic index. Thus, provided herein are short antisense compounds comprising high-affinity nucleotide modifications useful for reducing a target RNA in vivo. Such short antisense compounds are effective at lower doses than previously described antisense compounds, allowing for a reduction in toxicity and cost of treatment. In addition, the described short antisense compounds have greater potential for oral dosing.
대표청구항
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1. A method of inhibiting a target nucleid acid in a cell in an animal comprising administering to the animal a compound comprising a short antisense oligonucleotide consisting of 12 to 14 linked nucleosides and having: a gap region consisting of 8 to 12 linked 2′-deoxynucleosides;a 5′-wing region a
1. A method of inhibiting a target nucleid acid in a cell in an animal comprising administering to the animal a compound comprising a short antisense oligonucleotide consisting of 12 to 14 linked nucleosides and having: a gap region consisting of 8 to 12 linked 2′-deoxynucleosides;a 5′-wing region adjacent to the gap region at the 5′ side of the gap region and consisting of 1 to 3 linked modified nucleosides; anda 3′-wing region adjacent to the gap region at the 3′ side of the gap region and consisting of 1 to 3 linked modified nucleosides; whereinat least one modified nucleoside of one or both of the 5′-wing region and the 3′-wing region is a high-affinity modified monomer; and thereby inhibiting the target nucleic acid in the cell in the animal. 2. The method of claim 1, wherein the short antisense oligonucleotide consists of 12 linked nucleosides. 3. The method of claim 1, wherein the short antisense oligonucleotide consists of 13 linked nucleosides. 4. The method of claim 1, wherein the short antisense oligonucleotide consists of 14 linked nucleosides. 5. The method of claim 1, wherein the gap region consists of 8 linked 2′-deoxynucleosides. 6. The method of claim 1, wherein the gap region consists of 9 linked 2′-deoxynucleosides. 7. The method of claim 1, wherein the gap region consists of 10 linked 2′-deoxynucleosides. 8. The method of claim 1, wherein the gap region consists of 11 linked 2′-deoxynucleosides. 9. The method of claim 1, wherein the gap region consists of 12 linked 2′-deoxynucleosides. 10. The method of claim 1, wherein the short antisense oligonucleotide has a motif selected from 1-10-1; 2-10-1; 1-10-2; 2-10-2; and 2-8-2 wherein, the first number represents the number of modified nucleosides in the 5′-wing region, the second number represents the number of linked 2′-deoxynucleosides in the gap region, and the third number represents the number of modified nucleosides in the 3′-wing region. 11. The method of claim 10, wherein the motif is selected from 1-10-1; 2-10-2; and 2-8-2. 12. The method of claim 1, wherein the short antisense compound comprises at least one modified internucleoside linkage. 13. The method claim 12, wherein the short antisense compound comprises at least one phosphorothioate linkage. 14. The method of claim 12, wherein each internucleoside linkage of the short antisense oligonucleotide is a modified internucleo side linkage. 15. The method claim 14, wherein each modified internucleoside linkage is a phosphorothioate linkage. 16. The method of claim 1, wherein each modified nucleoside of one or both of the 5′-wing region and the 3′-wing region is a sugar-modified nucleotide comprising a bridge between the 4′ and 2′ position of the sugar. 17. The method of claim 1, wherein each modified nucleoside of both the 5′-wing region and the 3′-wing region is a sugar-modified nucleotide comprising a bridge between the 4′ and 2′ position of the sugar. 18. The method of claim 17, wherein the short antisense oligonucleotide consists of 12 linked nucleosides. 19. The method of claim 17, wherein the short antisense oligonucleotide consists of 13 linked nucleosides. 20. The method of claim 17, wherein the short antisense oligonucleotide consists of 14 linked nucleosides. 21. The method of claim 17, wherein the gap region consists of 8 linked 2′-deoxynucleosides. 22. The method of claim 17, wherein the gap region consists of 9 linked 2′-deoxynucleosides. 23. The method of claim 17, wherein the gap region consists of 10 linked 2′-deoxynucleosides. 24. The method of claim 17, wherein the gap region consists of 11 linked 2′-deoxynucleosides. 25. The method of claim 17, wherein the gap region consists of 12 linked 2′-deoxynucleosides. 26. The method of claim 17, wherein the short antisense oligonucleotide has a motif selected from 1-10-1; 2-10-1; 1-10-2; 2-10-2; 3-8-3; 2-8-3; 3-8-2; and 2-8-2 wherein, the first number represents the number of modified nucleosides in the 5′-wing region, the second number represents the number of 2′-deoxynucleosides in the gap region, and the third number represents the number of modified nucleosides in the 3′-wing region. 27. The method of claim 26, wherein the motif is selected from 1-10-1; 2-10-2; and 2-8-2. 28. The method of claim 17, wherein the short antisense compound comprises at least one modified internucleoside linkage. 29. The method claim 28, wherein the short antisense compound comprises at least one phosphorothioate linkage. 30. The method of claim 28, wherein each internucleoside linkage of the short antisense oligonucleotide is a modified internucleo side linkage. 31. The method claim 30, wherein each modified internucleoside linkage is a phosphorothioate linkage. 32. The method of claim 1, wherein the target nucleic acid is a target mRNA. 33. The method of claim 1, wherein the target nucleic acid is a target pre-mRNA. 34. The method of claim 1, wherein the target nucleic acid is from an infectious agent. 35. The method of claim 1, wherein the target nucleic acid is cleaved. 36. The method of claim 1, wherein the animal is a human. 37. The method of claim 1, wherein each high-affinity modified monomer is a 2′-modified nucleotide. 38. The method of claim 37, wherein each high-affinity modified monomer is a bicyclic nucleotide. 39. The method of claim 37, wherein each 2′-modified nucleotide comprises a 2′ modification independently selected from halogen, allyl, amino, azido, thio, O-allyl, O—C1-C10 alkyl, —OCF3, O—(CH2)2—O—CH3, 2′-O(CH2)2SCH3, O—(CH2)2—O—N(Rm)(Rn) or O—CH2—C(═O)—N(Rm)(Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. 40. The method of claim 1, wherein at least one modified nucleoside of one or both of the 5′-wing region and the 3′-wing region comprises a 2′-O(CH2)2OCH3 substituent. 41. The method of claim 16, wherein each of said bridges independently comprises 1 or from 2 to 4 linked groups independently selected from —[C(R1)(R2)]n—, —C(R1)═C(R2)—, —C(R1)═N—, —C(═NR1)—, —C(═O)—, —C(═S)—, —O—, —Si(R1)2—, —S(═O)x— and —N(R1)—; wherein x is 0, 1, or 2;n is 1, 2, 3, or 4;each R1 and R2 is, independently, H, a protecting group, 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, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)2-J1), or sulfoxyl (S(═O)-J1); andeach J1 and J2 is, independently, H, 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, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C1-C12 aminoalkyl, substituted C1-C12 aminoalkyl or a protecting group. 42. The method of claim 41, wherein at least one bridge comprises 4′-CH2—O -2′. 43. The method of claim 17, wherein each of said bridges independently comprises 1 or from 2 to 4 linked groups independently selected from —[C(R1)(R2)]n—, —C(R1)═C(R2)—, —C(R1)═N—, —C(═NR1)—, —C(═O)—, —C(═S)—, —O—, —Si(R1)2—, —S(═O)x— and —N(R1)—; wherein x is 0, 1, or 2;n is 1, 2, 3, or 4;each R1 and R2 is, independently, H, a protecting group, 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, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)2-J1), or sulfoxyl (S(═O)-J1); andeach J1 and J2 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C2o aryl, substituted C5-C20 aryl, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C1-C12 aminoalkyl, substituted C1-C12 aminoalkyl or a protecting group. 44. The method of claim 43, wherein at least one bridge comprises 4′-CH2—O-2′.
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