Methods for treatment of amyotrophic lateral sclerosis with follistatin fusion proteins
The disclosure provides, in part, follistatin polypeptides that are suitable for use in local administration and methods for use.
1. A method of treating amyotrophic lateral sclerosis (ALS) in a patient, the method comprising administering an effective amount of a follistatin fusion protein by an intramuscular route of administration to a targeted muscle of a patient in need thereof, wherein the follistatin fusion protein comprises a first amino acid sequence and a second amino acid sequence, wherein the first amino acid sequence consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 15 and 16, wherein the second amino acid sequence comprises a constant domain of an immunoglobulin G (IgG), wherein a linker directly connects the C-terminal portion of the first amino acid sequence to the N-terminal portion of the second amino acid sequence, and wherein the linker is 1-10 amino acids in length.
2. The method of claim 1 , wherein the increased muscle size or strength occurs in the targeted muscle.
3. The method of claim 1 , wherein the follistatin fusion protein does not have a substantial systemic effect on muscle size or strength.
4. The method of claim 1 , wherein the follistatin fusion protein is administered to only one targeted muscle.
5. The method of claim 1 , wherein the follistatin fusion protein is administered to more than one targeted muscle.
6. The method of claim 1 , wherein a muscle that is contralateral to a targeted muscle does not substantially increase in size or strength.
7. The method of claim 1 , wherein the follistatin fusion protein binds to one or more ligands selected from the group consisting of: myostatin, growth differentiation factor 11 (GDF-11), activin A and activin B with a dissociation constant (K D ) less than 1 nM, 100 pM, 50 pM or10 pM.
8. The method of claim 1 , wherein the follistatin fusion protein forms a dimer.
9. The method of claim 8 , wherein the follistatin fusion protein comprises an Fc portion of an IgG.
10. The method of claim 1 , wherein the follistatin fusion protein does not mediate substantial antibody-dependent cell-mediated toxicity (ADCC).
11. The method of claim 1 , wherein the follistatin fusion protein does not mediate substantial complement-dependent cytotoxicity (CDC).
12. The method of claim 1 , wherein the follistatin fusion protein comprises the amino acid sequence of SEQ ID NO: 43, but wherein the final (carboxy-terminal) lysine (K) of SEQ ID NO: 43 is optionally absent.
13. The method of claim 12 , wherein the final (carboxy-terminal) lysine (K) of SEQ ID NO: 43 is absent.
14. The method of claim 1 , wherein the follistatin fusion protein comprises the amino acid sequence of SEQ ID NO: 42, but wherein the final (carboxy-terminal) lysine (K) of SEQ ID NO: 42 is optionally absent.
15. The method of claim 14 , wherein the final (carboxy-terminal) lysine (K) of SEQ ID NO: 42 is absent.
16. The method of claim 1 , wherein the constant domain of the IgG is selected so as to mediate no substantial antibody-dependent cell-mediated cytotoxicity (ADCC) and/or no substantial complement dependent cytotoxicity (CDC).
17. The method of claim 1 , wherein the method causes no substantial effect in the patient on a measure selected from the group consisting of: serum follicle stimulating hormone (FSH) levels, liver size, hematocrit and reticulocyte levels.
18. The method of claim 1 , wherein the constant domain of the IgG is a constant domain of an IgG1.
19. The method of claim 18 , wherein the constant domain of the IgG1 comprises the amino acid sequence of SEQ ID NO: 17.
20. The method of claim 1 , wherein the constant domain of the IgG is a constant domain of an IgG2.
21. The method of claim 20 , wherein the constant domain of the IgG2 comprises the amino acid sequence of SEQ ID NO: 18.
22. The method of claim 1 , wherein the linker comprises the sequence of SEQ ID NO: 46.
23. The method of claim 21 , wherein the linker comprises the sequence of SEQ ID NO: 46.
24. The method of claim 1 , wherein the linker consists of the sequence of SEQ ID NO: 46.
25. The method of claim 21 , wherein the linker consists of the sequence of SEQ ID NO: 46.
26. The method of claim 1 , wherein the follistatin fusion protein comprises the amino acid sequence of SEQ ID NO: 42.
27. The method of claim 1 , wherein the follistatin fusion protein comprises the amino acid sequence of SEQ ID NO: 43.