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):	Prakash Thazha P., Seth Punit P., Swayze Eric E.
Assignee:	Ionis Pharmaceuticals, Inc.
Application Number:	US15687306
Patent Claims:	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 claim 2 , a constrained ethyl claim 2 , a 3′-fluoro-HNA or a 4′-(CH)—O-2′ bridge claim 2 , 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 claim 1 , 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 claim 1 , 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.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 to the subject having transthyretin amyloidosis.38. A method of treating transthyretin amyloidosis in a subject comprising administering the compound of to the subject having transthyretin amyloidosis.39. A method of treating transthyretin amyloidosis in a subject comprising administering the compound of to the subject having transthyretin amyloidosis.40. The method of claim 37 , wherein the transthyretin amyloidosis is senile systemic amyloidosis (SSA) claim 37 , familial amyloid polyneuropathy (FAP) claim 37 , or familial amyloid cardiopathy (FAC).41. The method of claim 38 , wherein the transthyretin amyloidosis is senile systemic amyloidosis (SSA) claim 38 , familial amyloid polyneuropathy (FAP) claim 38 , or familial amyloid cardiopathy (FAC).42. The method of claim 39 , wherein the transthyretin amyloidosis is senile systemic amyloidosis (SSA) claim 39 , familial amyloid polyneuropathy (FAP) claim 39 , or familial amyloid cardiopathy (FAC).43. A method of reducing expression of transthyretin in a cell comprising contacting the cell with the compound of .44. A method of reducing expression of transthyretin in a cell comprising contacting the cell with the compound of .45. A method of reducing expression of transthyretin in a cell comprising contacting the cell with the compound of .46. A method of reducing expression of transthyretin in a subject comprising administering the compound of to the subject.47. A method of reducing expression of transthyretin in a subject comprising administering the compound of to the subject.48. A method of reducing expression of transthyretin in a subject comprising administering the compound of 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 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 .53. A method of reducing expression of transthyretin in a subject comprising administering the compound of to the subject.