Compositions and methods for modulating complement factor B expression

• US 10,280,423 B2
• Filed: 05/01/2015
• Issued: 05/07/2019
• Est. Priority Date: 05/01/2014
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Prakash, Thazha P., Seth, Punit P., Swayze, Eric E., Grossman, Tamar R., McCaleb, Michael L., Freier, Susan M.
• Primary Examiner(s): Whiteman, Brian
• Application Number:
  US15/307,526
• Publication Number:
  US 20170159055A1
• Time in Patent Office: 1,467 Days
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12Y 304/21047 Alternative-complement-pathway C3/C5 convertase (3.4.21.47), i.e. properdin factor B

Abstract

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.

Claims

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′

-(CH₂)—

O-2′

(LNA);

4′

-(CH₂)₂—

O-2′

(ENA); and

4′

-CH(CH₃)—

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:

27. A compound having the formula:

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).

28. A compound having the formula:

29. A compound having the formula:

30. A compound having the formula: