Compounds and methods for modulating expression of PCSK9
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/70
C07H-021/02
C07H-021/04
C12Q-001/68
C12N-005/00
출원번호
US-0299572
(2007-05-07)
등록번호
US-8143230
(2012-03-27)
국제출원번호
PCT/US2007/068404
(2007-05-07)
§371/§102 date
20090223
(20090223)
국제공개번호
WO2007/143315
(2007-12-13)
발명자
/ 주소
Bhanot, Sanjay
Geary, Richard S.
McKay, Robert
Monia, Brett P.
Seth, Punit P.
Siwkowski, Andrew M.
Swayze, Eric
Wancewicz, Edward
출원인 / 주소
ISIS Pharmaceuticals, Inc.
대리인 / 주소
Drinker Biddle & Reath LLP
인용정보
피인용 횟수 :
21인용 특허 :
55
초록▼
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▼
1. A short antisense compound 8 to 14 monomers in length, comprising a 2′-deoxyribonucleotide gap region flanked on each side by at least one wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers and wherein the short antisense compound is targeted to a nucleotide en
1. A short antisense compound 8 to 14 monomers in length, comprising a 2′-deoxyribonucleotide gap region flanked on each side by at least one wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers and wherein the short antisense compound is targeted to a nucleotide encoding PCSK9. 2. The short antisense compound of claim 1, wherein said high-affinity modified monomers are sugar-modified nucleotides. 3. The short antisense compound of claim 2, wherein at least one of the sugar-modified nucleotides comprises a bridge between the 4′ and the 2′ position of the sugar. 4. The short antisense compound of claim 2, wherein each of said high-affinity modified nucleotides confers a ΔTm of 1 to 4 degrees per nucleotide. 5. The short antisense compound of claim 2, wherein each of said sugar-modified nucleotides comprises a 2′-substituent group that is other than H or OH. 6. The short antisense compound of claim 5, wherein at least one of said sugar-modified nucleotides is a 4′ to 2′ bridged bicyclic nucleotide. 7. The short antisense compound of claim 5, wherein each of the 2′-substituent groups is, independently, alkoxy, substituted alkoxy, or halogen. 8. The short antisense compound of claim 7, wherein each of the 2′-substituent groups is OCH2CH2OCH3. 9. The short antisense compound claim 3, wherein the conformation of each of said sugar-modified nucleotides is, independently, β-D or α-L. 10. The short antisense compound claim 3, 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(Ri)—; whereinx 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, COOJI, 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. 11. The short antisense compound of claim 10, wherein each of said bridges is, independently, 4′-CH2-2′, 4′-(CH2)2-2′, 4′-CH2—O-2′, 4′-(CH2)2—O-2′, 4′-CH2—O—N(R1)-2′ and 4′-CH2—N(R1)—O-2′- wherein each R1 is, independently, H, a protecting group or C1-C12 alkyl. 12. The short antisense compound of claim 1, wherein each of the high-affinity modified monomer is independently selected from bicyclic nucleotides or other 2′-modified nucleotides. 13. The short antisense compound of claim 12, wherein the 2′-modified nucleotides are 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. 14. The short antisense compound of claim 13, wherein the 2′-modified nucleotide is a 2′-OCH2CH2OCH3 nucleotide. 15. The short antisense compound of claim 1, wherein at least one monomeric linkage is a modified monomeric linkage. 16. The antisense compound of claim 15, wherein the modified monomeric linkage is a phosphorothioate linkage. 17. The short antisense compound of claim 1, wherein each monomeric linkage is a phosphorothioate internucleoside linkage. 18. The short antisense compound of claim 1, that is 8-13 monomers in length. 19. The short antisense compound of claim 18 that is 8-10 monomers in length. 20. The short antisense compound of claim 18 that is 11-13 monomers in length. 21. The short antisense compound of claim 1 that is 11-12 monomers in length. 22. The short antisense compound of claim 18 that is 9-10 monomers in length. 23. The short antisense compound of claim 18 that is 9-13 monomers in length. 24. The short antisense compound of claim 18 that is 10-13 monomers in length. 25. The short antisense compound of claim 18 that is 9-12 monomers in length. 26. The short antisense compound of claim 18 that is 10-12 monomers in length. 27. The short antisense compound of claim 18 that is 9-11 monomers in length. 28. The short antisense compound of claim 18 that is 10-11 monomers in length. 29. The short antisense compound of claim 18 that is 8 monomers in length. 30. The short antisense compound of claim 18 that is 9 monomers in length. 31. The short antisense compound of claim 18 that is 10 monomers in length. 32. The short antisense compound of claim 18 that is 11 monomers in length. 33. The short antisense compound of claim 18 that is 12 monomers in length. 34. The short antisense compound of claim 18 that is 13 monomers in length. 35. The short antisense compound of claim 1 that is 14 monomers in length. 36. The short antisense compound of claim 1, having a motif selected from 1-12-1; 2-10-2; 1-10-1; 1-10-2; 1-9-1; 1-9-2; 2-9-1; 2-8-1; 2-7-1; 2-7-2; 2-6-3; 2-7-2; 2-6-2; 3-8-3; 2-8-2; 1-8-1; 3-6-3; and 1-6-1 wherein, the first number represents the number of monomers in the 5′-wing, the second number represents the number of monomers in the gap, and the third number represents the number of monomers in the 3′ wing. 37. The short antisense compound of claim 36 wherein the motif is selected from 1-10-1; 2-10-2; and 1-9-2. 38. The short antisense compound of claim 1 having a motif selected from 1-1-10-2, 1-1-8-2, 1-1-6-3, and 1-2-8-2, wherein the first number represents the number of monomers in a first 5′ wing, the second number represents the number of monomers in a second 5′ wing, the third number represents the number of monomers in the gap, and the fourth number represents the number of monomers in the 3′ wing. 39. The short antisense compound of claim 1 having a motif selected from 2-10-1-1, 2-8-1-1, 3-6-1-1, and 2-8-2-1, wherein the first number represents the number of monomers in the 5′ wing, the second number represents the number of monomers in the gap, the third number represents the number of monomers in a first 3′ wing, and the fourth number represents the number of monomers in a second 3′ wing. 40. The short antisense compound of claim 1 having a motif selected from 1-1-8-1-1; 2-1-6-1-1; and 1-2-8-2-1, wherein the first number represents the number of monomers in a first 5′ wing, the second number represents the number of monomers in a second 5′ wing, the third number represents the number of monomers in the gap, the fourth number represents the number of monomers in a first 3′ wing and the fifth number represents the number of monomers in a second 3′ wing. 41. A method of inhibiting PCSK9 expression comprising contacting a nucleic acid encoding PCSK9 with the short antisense compound of claim 1. 42. The method of claim 41 wherein the PCSK9 nucleic acid is in a cell. 43. The method of claim 42, wherein the PCSK9 nucleic acid is in an animal, and wherein the method further comprises administering the short antisense compound of claim 1 to the animal. 44. The method of claim 43, wherein the animal is a human. 45. The method of claim 43, wherein said contacting decreases total serum cholesterol, serum LDL, serum VLDL, serum HDL, serum triglycerides, serum apolipoprotein(s) and/or free fatty acids in the animal. 46. The method of claim 43, wherein inhibiting PCSK9 expression treats a cardiovascular disorder in the animal.
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