Compositions and methods for modulating complement factor B expression

1. A modified single-stranded oligonucleotide covalently attached to a conjugate group, wherein the modified single-stranded oligonucleotide consists of 10 to 30 linked nucleosides and has a nucleobase sequence comprising at least 8 contiguous nucleobases of SEQ ID NO: 440, wherein the conjugate group covalently attached to the modified single-stranded oligonucleotide comprises:

2. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified oligonucleotide consists of 20 to 30 linked nucleosides and has a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO: 440.

3. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 440.

4. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides having a nucleobase sequence comprising SEQ ID NO: 440, wherein the modified oligonucleotide comprises:

a gap segment consisting of linked deoxynucleosides;

a 5′ wing segment consisting of linked nucleosides; and

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.

5. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 440, wherein the modified oligonucleotide comprises

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of five linked nucleosides; and

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; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine.

6. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified oligonucleotide consists of 16 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 598, wherein the modified oligonucleotide comprises

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment;

wherein the 5′ wing segment comprises a 2′-O-methoxyethyl sugar, 2′-O-methoxyethyl sugar, and cEt sugar in the 5′ to 3′ direction; wherein the 3′ wing segment comprises a cEt sugar, cEt sugar, and 2′-O-methoxyethyl sugar in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.

7. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the oligonucleotide is at least 85% complementary to SEQ ID NO: 1.

8. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase.

9. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 8 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

10. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 9 , wherein the modified oligonucleotide comprises at least 1 phosphodiester internucleoside linkage.

11. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 10 , wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.

12. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 9 , wherein each internucleoside linkage of the modified oligonucleotide comprises a phosphorothioate internucleoside linkage.

13. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 8 , wherein the modified sugar is a bicyclic sugar.

14. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 13 , wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 ) 2 —O-2′ (ENA); and 4′-CH(CH 3 )—O-2′ (cEt).

15. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 8 , wherein the modified sugar is 2′-O-methoxyethyl.

16. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 8 , wherein the modified nucleobase is a 5-methylcytosine.

17. A modified double-stranded oligonucleotide, comprising the modified single stranded oligonucleotide covalently attached to a conjugate group of claim 1 , and a second single stranded oligonucleotide hybridized to said modified single stranded oligonucleotide.

18. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified single-stranded oligonucleotide comprises ribonucleotides.

19. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified single-stranded oligonucleotide comprises deoxyribonucleotides.

20. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide.

21. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide.

22. A method of treating or ameliorating a disease associated with dysregulation of the complement alternative pathway in a subject comprising administering to the subject the modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , thereby treating or ameliorating the disease.

23. The method of claim 22 , wherein the disease is macular degeneration, age related macular degeneration (AMD), wet AMD, dry AMD, or Geographic Atrophy.

24. The method of claim 22 , wherein the disease is a kidney disease.

25. The method of claim 24 , wherein the kidney disease is lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS).

26. A compound having the formula:

or a pharmaceutically acceptable salt thereof;

wherein either R 1 is OCH 2 CH 2 OCH 3 (MOE) and R 2 is H; or R 1 and R 2 together form a bridge, wherein R 1 is —O— and R 2 is —CH 2 —, —CH(CH 3 )—, or —CH 2 CH 2 —, and R 1 and R 2 are directly connected such that the resulting bridge is selected from: —O—CH 2 —, —O—CH(CH 3 )—, and —O—CH 2 CH 2 —;

and for each pair of R 3 and R 4 on the same ring, independently for each ring: either R 3 is selected from H and —OCH 2 CH 2 OCH 3 and R 4 is H; or R 3 and R 4 together form a bridge, wherein R 3 is —O—, and R 4 is —CH 2 —, —CH(CH 3 )—, or —CH 2 CH 2 — and R 3 and R 4 are directly connected such that the resulting bridge is selected from: —O—CH 2 —, —O—CH(CH 3 )—, and —O—CH 2 CH 2 —;

and R 5 is selected from H and —CH 3 ;

and Z is selected from S − and O − .

27. A compound having the formula:

or a pharmaceutically acceptable salt thereof.

28. A compound having the formula:

or a pharmaceutically acceptable salt thereof.

29. A compound having the formula:

or a pharmaceutically acceptable salt thereof.

30. A compound having the formula:

or a pharmaceutically acceptable salt thereof.

31. A composition comprising the compound of claim 27 or the pharmaceutically acceptable salt thereof.

32. The compound of claim 27 , wherein the pharmaceutically acceptable salt is sodium.

33. A method of treating or ameliorating a disease associated with dysregulation of the complement alternative pathway in a subject comprising administering to the subject the compound of claim 27 , or pharmaceutically acceptable salt thereof, thereby treating or ameliorating the disease.

34. The method of claim 33 , wherein the disease is macular degeneration, age related macular degeneration (AMD), wet AMD, dry AMD, or Geographic Atrophy.

35. The method of claim 33 , wherein the disease is a kidney disease.

36. The method of claim 35 , wherein the kidney disease is lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS).