Methods of treating non-alcoholic steatohepatitis using FGF21 mutants
The invention provides methods for treating non-alcoholic steatohepatitis (NASH) using FGF21 mutant polypeptides.
1. A method of treating non-alcoholic steatohepatitis (NASH) comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a polypeptide comprising the amino acid sequence of SEQ ID NO:4 comprising:
(a) a substitution of an arginine residue for the leucine residue at position 98;
(b) a substitution of a glycine residue for the proline residue at position 171; and
(c) a substitution of a glutamic acid residue for the alanine residue at position 180.
2. The method of claim 1 , wherein the polypeptide comprises 1 to 10 amino acid residues fused to the C-terminus of the polypeptide.
3. The method of claim 1 , wherein the polypeptide is covalently linked to one or more polymers.
4. The method of claim 3 , wherein the polypeptide is covalently linked to PEG.
5. The method of claim 1 , wherein the polypeptide is fused to a heterologous amino acid sequence.
6. The method of claim 5 , wherein the polypeptide is fused to the heterologous amino acid sequence via a linker.
7. The method of claim 6 , wherein the linker comprises GGGGGSGGGSGGGGS (SEQ ID NO: 23).
8. The method of claim 6 , wherein the linker comprises GGGGSGGGGSGGGGS (SEQ ID NO: 31).
9. The method of claim 8 , wherein the heterologous amino acid sequence is an IgG constant domain or fragment thereof.
10. The method of claim 9 , wherein the IgG constant domain comprises the amino acid sequence of SEQ ID NO:13.
11. The method of claim 6 , wherein the heterologous amino acid sequence is an IgG constant domain or fragment thereof.
12. The method of claim 11 , wherein the IgG constant domain comprises the amino acid sequence of SEQ ID NO:13.