Compositions and methods for modulating complement factor B expression
The present embodiments provide methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway by administering a Complement Factor B (CFB) specific inhibitor to a subject.
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 the nucleobase sequence of SEQ ID NO: 455, and 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 single-stranded oligonucleotide has:
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.
3. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified single-stranded oligonucleotide is at least 85% complementary to SEQ ID NO: 1.
4. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 1 , wherein the modified single-stranded oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase.
5. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 4 , wherein the modified single-stranded oligonucleotide comprises at least one modified internucleoside linkage.
6. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 5 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
7. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 6 , wherein the modified single-stranded oligonucleotide comprises at least 1 phosphodiester internucleoside linkage.
8. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 7 , wherein each internucleoside linkage of the modified single-stranded oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.
9. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 4 , wherein each internucleoside linkage of the modified single-stranded oligonucleotide comprises a phosphorothioate internucleoside linkage.
10. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 4 , wherein the modified sugar is a bicyclic sugar.
11. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 10 , 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).
12. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 4 , wherein the modified sugar is 2′-O-methoxyethyl.
13. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 4 , wherein the modified nucleobase is 5-methylcytosine.
14. 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.
15. 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.
16. 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.
17. A method of treating 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 , or a pharmaceutically acceptable salt thereof, thereby treating the disease.
18. The method of claim 17 , wherein the disease is macular degeneration, age related macular degeneration (AMD), wet AMD, dry AMD, or Geographic Atrophy.
19. The method of claim 17 , wherein the disease is a kidney disease.
20. The method of claim 19 , wherein the kidney disease is lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, IgA nephropathy, or atypical hemolytic uremic syndrome (aHUS).
21. A modified single-stranded oligonucleotide covalently attached to a conjugate group, wherein the modified single-stranded oligonucleotide consists of 20 to 30 linked nucleosides and has a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO: 455, and wherein the conjugate group covalently attached to the modified single-stranded oligonucleotide comprises:
22. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 21 , wherein the modified single-stranded oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 455.
23. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 21 , wherein the modified single-stranded oligonucleotide consists of 20 linked nucleosides and has a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 455, and wherein the modified single-stranded oligonucleotide has:
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 of the modified single-stranded oligonucleotide is a phosphorothioate linkage, and wherein each cytosine is 5-methylcytosine.
24. The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 23 , wherein the modified single-stranded oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 455.
25. A method of treating 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 23 , or a pharmaceutically acceptable salt thereof, thereby treating the disease.
26. The method of claim 25 , wherein the disease is macular degeneration, age related macular degeneration (AMD), wet AMD, dry AMD, or Geographic Atrophy.
27. The method of claim 26 , wherein the disease is a kidney disease.
28. The method of claim 27 , wherein the kidney disease is lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, IgA nephropathy, or atypical hemolytic uremic syndrome (aHUS).