Compositions and methods for modulating TTR expression
Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.
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′-(CH 2 ) 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.