Claims for Patent: 10,683,499

Summary for Patent: 10,683,499

Title:	Compositions and methods for modulating TTR expression
Abstract:	Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.
Inventor(s):	Thazha P. Prakash, Punit P. Seth, Eric E. Swayze
Assignee:	Glaxo Group Ltd , Ionis Pharmaceuticals Inc
Application Number:	US15/687,306
Patent Claims:	1. A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides and wherein the nucleobase sequence of the modified oligonucleotide comprises a portion of at least 8 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 2, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 2; and wherein the conjugate group comprises: 2. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modified sugar. 3. The compound of claim 2, wherein at least one modified sugar is a bicyclic sugar. 4. The compound of claim 2, wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl, a 3′-fluoro-HNA or a 4′-(CH2)n—O-2′ bridge, wherein n is 1 or 2. 5. The compound of claim 2, wherein at least one modified sugar is 2′-O-methoxyethyl. 6. The compound of claim 1, wherein at least one nucleoside comprises a modified nucleobase. 7. The compound of claim 6, wherein the modified nucleobase is a 5-methylcytosine. 8. The compound of claim 1, wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. 9. The compound of claim 1, wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide. 10. The compound of claim 1, wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage. 11. The compound of claim 10, wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages. 12. The compound of claim 10, wherein the modified oligonucleotide comprises at least two phosphorothioate internucleoside linkages. 13. The compound of claim 1, wherein the modified oligonucleotide is single-stranded. 14. The compound of claim 1, wherein the modified oligonucleotide is double stranded. 15. The compound of claim 1, wherein the modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5′ wing segment consisting of linked nucleosides; a 3′ wing segment consisting of linked nucleosides; wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 16. The compound of claim 15, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 17. The compound of claim 16, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 18. The compound of claim 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 2. 19. The compound of claim 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO: 2. 20. The compound of claim 1, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 2. 21. The compound of claim 1, wherein the modified oligonucleotide comprises the nucleobase sequence of any of SEQ ID NOs: 12-19. 22. The compound of claim 1, wherein the modified oligonucleotide consists of linked nucleosides consisting of the nucleobase sequence of any of SEQ ID NOs: 12-19. 23. The compound of claim 1, wherein the modified oligonucleotide consists of 20 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 12, and wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides; a 5′ wing segment consisting of five linked nucleosides; a 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, and wherein each cytosine residue is a 5-methylcytosine. 24. The compound of claim 1, wherein the modified oligonucleotide consists of 20 linked nucleosides having a nucleobase sequence consisting of any one of SEQ ID NOs: 13-19, and wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides; a 5′ wing segment consisting of five linked nucleosides; a 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, and wherein each cytosine residue is a 5-methylcytosine. 25. The compound of claim 23, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 26. The compound of claim 24, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 27. The compound of claim 25, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 28. The compound of claim 26, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 29. The compound of claim 23, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage. 30. The compound of claim 24, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage. 31. The compound of claim 23, wherein the modified oligonucleotide is single-stranded. 32. The compound of claim 24, wherein the modified oligonucleotide is single-stranded. 33. A compound having the formula: or a pharmaceutically acceptable salt thereof. 34. A compound having the formula: or a pharmaceutically acceptable salt thereof. 35. A composition comprising the compound of claim 33, and a pharmaceutically acceptable carrier or diluent. 36. A composition comprising the compound of claim 34, and a pharmaceutically acceptable carrier or diluent. 37. A method of treating transthyretin amyloidosis in a subject comprising administering the compound of claim 1 to the subject having transthyretin amyloidosis. 38. A method of treating transthyretin amyloidosis in a subject comprising administering the compound of claim 33 to the subject having transthyretin amyloidosis. 39. A method of treating transthyretin amyloidosis in a subject comprising administering the compound of claim 34 to the subject having transthyretin amyloidosis. 40. The method of claim 37, wherein the transthyretin amyloidosis is senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), or familial amyloid cardiopathy (FAC). 41. The method of claim 38, wherein the transthyretin amyloidosis is senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), or familial amyloid cardiopathy (FAC). 42. The method of claim 39, wherein the transthyretin amyloidosis is senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), or familial amyloid cardiopathy (FAC). 43. A method of reducing expression of transthyretin in a cell comprising contacting the cell with the compound of claim 1. 44. A method of reducing expression of transthyretin in a cell comprising contacting the cell with the compound of claim 33. 45. A method of reducing expression of transthyretin in a cell comprising contacting the cell with the compound of claim 34. 46. A method of reducing expression of transthyretin in a subject comprising administering the compound of claim 1 to the subject. 47. A method of reducing expression of transthyretin in a subject comprising administering the compound of claim 33 to the subject. 48. A method of reducing expression of transthyretin in a subject comprising administering the compound of claim 34 to the subject. 49. The compound of claim 34, wherein said pharmaceutically acceptable salt is a sodium salt. 50. A composition comprising the compound of claim 49, and a pharmaceutically acceptable carrier or diluent. 51. A method of treating transthyretin amyloidosis in a subject comprising administering the compound of claim 49 to the subject having transthyretin amyloidosis. 52. A method of reducing expression of transthyretin in a cell comprising contacting the cell with the compound of claim 49. 53. A method of reducing expression of transthyretin in a subject comprising administering the compound of claim 49 to the subject.