Methods and uses for modulating bile acid homeostasis and treatment of bile acid disorders and diseases
Provided herein are methods of modulating bile acid homeostasis or treating a bile-acid related or associated disorder, comprising using variants and fusions of fibroblast growth factor 19 (FGF19), variants and fusions of fibroblast growth factor 21 (FGF21), fusions of FGF19 and/or FGF21, and variants or fusions of FGF19 and/or FGF21 proteins and peptide sequences (and peptidomimetics), in combination with agents effective in modulating bile acid homeostasis or treating a bile-acid related or associated disorder.
1. A method of reducing bile acid synthesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of
(i) a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:70, and
(ii) at least one additional agent, wherein the additional agent is an anti-CD20 agent, an anti-CD80 agent, an anti-cytokine antibody, an anti-retroviral therapy, an apical sodium bile acid transporter (ASBT) inhibitor, an autoimmune agent, azathioprine, cochicine, a CSCL10 neutralizing antibody, a CXCR3 ligand, cyclosporine, a cytokine anti-inflammatory drug (CSAID), a cytokine, a growth factor, a fibrate, a fish oil, an immune checkpoint inhibitor, or a non-steroidal anti-inflammatory drug (NSAID);
thereby reducing bile acid synthesis in the subject without inducing HGG hepatocellular carcinoma (HCC) formation.
2. The method of claim 1 , wherein the additional agent is an anti-CD20 agent.
3. The method of claim 1 , wherein the additional agent is an anti-CD80 agent.
4. The method of claim 1 , wherein the additional agent is an anti-cytokine antibody.
5. The method of claim 1 , wherein the additional agent is an anti-retroviral therapy.
6. The method of claim 1 , wherein the additional agent is an ASBT inhibitor.
7. The method of claim 1 , wherein the additional agent is an autoimmune agent.
8. The method of claim 1 , wherein the additional agent is azathioprine.
9. The method of claim 1 , wherein the additional agent is cochicine.
10. The method of claim 1 , wherein the additional agent is a CSCL10 neutralizing antibody.
11. The method of claim 1 , wherein the additional agent is a CXCR3 ligand.
12. The method of claim 1 , wherein the additional agent is cyclosporine.
13. The method of claim 1 , wherein the additional agent is a CSAID.
14. The method of claim 1 , wherein the additional agent is a cytokine.
15. The method of claim 14 , wherein the cytokine is IL-12.
16. The method of claim 1 , wherein the additional agent is a growth factor.
17. The method of claim 1 , wherein the additional agent is a fibrate.
18. The method of claim 1 , wherein the additional agent is a fish oil.
19. The method of claim 1 , wherein the additional agent is an immune checkpoint inhibitor.
20. The method of claim 1 , wherein the additional agent is a NSAID.
21. The method of claim 1 , wherein the subject has nonalcoholic steatohepatitis (NASH).
22. The method of claim 1 , wherein the subject has primary biliary cirrhosis (PBC).
23. The method of claim 1 , wherein the subject has cholestasis.
24. The method of claim 1 , wherein the subject has primary sclerosing cholangitis (PSC).
25. The method of claim 1 , wherein the subject has bile acid diarrhea (BAD) or bile acid malabsorption.
26. The method of claim 1 , wherein the subject has pregnancy intrahepatic cholestasis (PIC).
27. The method of claim 1 , wherein the subject has liver fibrosis.
28. The method of claim 1 , wherein the subject has nonalcoholic fatty liver disease (NAFLD).
29. The method of claim 1 , wherein the subject has cirrhosis.
30. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:70.
31. The method of claim 1 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:70.
32. A method of reducing bile acid synthesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of
(i) a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:70, and
(ii) at least one additional agent, wherein the additional agent is a farnesoid X receptor (FXR) agonist or a steroid;
thereby reducing bile acid synthesis in the subject without inducing HCC formation.
33. The method of claim 32 , wherein the additional agent is a FXR agonist.
34. The method of claim 32 , wherein the additional agent is a steroid.
35. The method of claim 32 , wherein the steroid is a glucocorticoid.
36. The method of claim 32 , wherein the subject has NASH.
37. The method of claim 32 , wherein the subject has PBC.
38. The method of claim 32 , wherein the subject has cholestasis.
39. The method of claim 32 , wherein the subject has PSC.
40. The method of claim 32 , wherein the subject has an error of bile acid synthesis.
41. The method of claim 32 , wherein the subject has BAD or bile acid malabsorption.
42. The method of claim 32 , wherein the subject has PIC.
43. The method of claim 32 , wherein the subject has liver fibrosis.
44. The method of claim 32 , wherein the subject has NAFLD.
45. The method of claim 32 , wherein the subject has cirrhosis.
46. The method of claim 32 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:70.
47. The method of claim 32 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:70.
48. A method of reducing bile acid synthesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of
(i) a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:70, and
(ii) at least one additional agent, wherein the additional agent is chenodeoxycholic acid (CDCA), obeticholic acid (OCA), or ursodeoxycholic acid (UDCA);
thereby reducing bile acid synthesis in the subject without inducing HCC formation.
49. The method of claim 48 , wherein the additional agent is CDCA.
50. The method of claim 48 , wherein the additional agent is OCA.
51. The method of claim 48 , wherein the additional agent is UDCA.
52. The method of claim 48 , wherein the subject has NASH.
53. The method of claim 48 , wherein the subject has PBC.
54. The method of claim 48 , wherein the subject has cholestasis.
55. The method of claim 48 , wherein the subject has PSC.
56. The method of claim 48 , wherein the subject has an error of bile acid synthesis.
57. The method of claim 48 , wherein the subject has BAD or bile acid malabsorption.
58. The method of claim 48 , wherein the subject has PIC.
59. The method of claim 48 , wherein the subject has liver fibrosis.
60. The method of claim 48 , wherein the subject has NAFLD.
61. The method of claim 48 , wherein the subject has cirrhosis.
62. The method of claim 48 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:70.
63. The method of claim 48 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:70.