[미국특허]
Modulation of transthyretin expression
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-015/11
C12N-015/113
A61K-031/712
출원번호
US-0717746
(2015-05-20)
등록번호
US-9399774
(2016-07-26)
발명자
/ 주소
Monia, Brett P.
Freier, Susan M.
Siwkowski, Andrew M.
Guo, Shuling
출원인 / 주소
Ionis Pharmaceuticals, Inc.
대리인 / 주소
Knobbe, Martens, Olson & Bear, LLP
인용정보
피인용 횟수 :
1인용 특허 :
232
초록
Provided herein are methods, compounds, and compositions for reducing expression of transthyretin mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate transthyretin amyloidosis, or a symptom thereof.
대표청구항▼
1. A method of treating transthyretin amyloidosis in an individual comprising administering to the individual a composition comprising an aqueous solution having a viscosity level less than 40 centipoise (cP), wherein the aqueous solution comprises a compound comprising a single-stranded modified ol
1. A method of treating transthyretin amyloidosis in an individual comprising administering to the individual a composition comprising an aqueous solution having a viscosity level less than 40 centipoise (cP), wherein the aqueous solution comprises a compound comprising a single-stranded modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 80, wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides;a 5′ wing segment consisting of five linked nucleosides; anda 3′ wing segment consisting of five linked nucleosides;wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine. 2. The method of claim 1, wherein the aqueous solution has a temperature of about 25° C. 3. The method of claim 1, wherein the aqueous solution has a viscosity level less than 15 centipoise (cP). 4. The method of claim 3, wherein the aqueous solution has a temperature of about 25° C. 5. The method of claim 1, wherein the aqueous solution has a viscosity level less than 12 centipoise (cP). 6. The method of claim 5, wherein the aqueous solution has a temperature of about 25° C. 7. The method of claim 1, wherein the aqueous solution has a viscosity level less than 10 centipoise (cP). 8. The method of claim 7, wherein the aqueous solution has a temperature of about 25° C. 9. The method of claim 1, wherein the aqueous solution consists of water and the compound, and the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC). 10. The method of claim 2, wherein the aqueous solution consists of water and the compound, and the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC). 11. The method of claim 3, wherein the aqueous solution consists of water and the compound, and the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC). 12. The method of claim 4, wherein the aqueous solution consists of water and the compound, and the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC). 13. The method of claim 5, wherein the aqueous solution consists of water and the compound, and the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC). 14. The method of claim 6, wherein the aqueous solution consists of water and the compound, and the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC). 15. The method of claim 7, wherein the aqueous solution consists of water and the compound, and the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC). 16. The method of claim 8, wherein the aqueous solution consists of water and the compound, and the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC). 17. A method comprising administering to an individual having transthyretin amyloidosis a tolerable amount of a compound comprising a single-stranded modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 80, wherein administering the tolerable amount of the compound increases plasma alanine transaminase (ALT) or aspartate transaminase (AST) levels in the individual by less than 4-fold and the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides;a 5′ wing segment consisting of five linked nucleosides; anda 3′ wing segment consisting of five linked nucleosides;wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine. 18. The method of claim 17, wherein the administering the tolerable amount of the compound increases plasma ALT or AST levels in the individual by less than 3-fold in the individual. 19. The method of claim 17, wherein the administering the tolerable amount of the compound increases plasma ALT or AST levels in the individual by less than 2-fold in the individual. 20. The method of claim 17, wherein administering the tolerable amount of the compound increases plasma ALT and AST levels in the individual by less than 4-fold. 21. The method of claim 17, wherein administering the tolerable amount of the compound increases plasma ALT and AST levels in the individual by less than 3-fold. 22. The method of claim 17, wherein administering the tolerable amount of the compound increases plasma ALT and AST levels in the individual by less than 2-fold. 23. The method of claim 17, wherein administering the tolerable amount of the compound increases plasma ALT levels in the individual by less than 4-fold. 24. The method of claim 17, wherein administering the tolerable amount of the compound increases plasma ALT levels in the individual by less than 3-fold. 25. The method of claim 17, wherein administering the tolerable amount of the compound increases plasma ALT levels in the individual by less than 2-fold. 26. The method of claim 17, wherein administering the tolerable amount of the compound increases plasma AST levels in the individual by less than 4-fold. 27. The method of claim 17, wherein administering the tolerable amount of the compound increases plasma AST levels in the individual by less than 3-fold. 28. The method of claim 17, wherein administering the tolerable amount of the compound increases plasma AST levels in the individual by less than 2-fold. 29. The method of claim 17, wherein administering the tolerable amount of the compound increases liver, spleen or kidney weight of the individual less than 30%. 30. The method of claim 17, wherein administering the tolerable amount of the compound treats, ameliorates, or slows progression of transthyretin amyloidosis in the individual. 31. The method of claim 17, wherein administering the tolerable amount of the compound reduces transthyretin mRNA or protein expression in the individual. 32. The method of claim 17, wherein the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP). 33. The method of claim 17, wherein the transthyretin amyloidosis is familial amyloid cardiopathy (FAC). 34. The method of claim 30, wherein administering the tolerable amount of the compound treats, ameliorates, or slows progression of familial amyloid polyneuropathy (FAP) in the individual. 35. The method of claim 30, wherein administering the tolerable amount of the compound treats, ameliorates, or slows progression of familial amyloid cardiopathy (FAC) in the individual. 36. A method of treating transthyretin amyloidosis in an individual comprising administering to the individual a compound consisting of a pharmaceutically acceptable salt of a single-stranded modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 80, wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides;a 5′ wing segment consisting of five linked nucleosides; anda 3′ wing segment consisting of five linked nucleosides;wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine. 37. The method of claim 36, wherein the pharmaceutically acceptable salt is a sodium salt. 38. The method of claim 37, wherein the pharmaceutically acceptable salt is a potassium salt. 39. The method of claim 36, wherein the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC). 40. The method of claim 37, wherein the transthyretin amyloidosis is familial amyloid polyneuropathy (FAP) or familial amyloid cardiopathy (FAC).
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