Follistatin in treating duchenne muscular dystrophy
The present invention provides, among other things, methods and compositions for treating muscular dystrophy, in particular, Duchenne muscular dystrophy (DMD). In some embodiments, a method according to the present invention includes administering to an individual who is suffering from or susceptible to DMD an effective amount of a recombinant follistatin protein such that at least one symptom or feature of DMD is reduced in intensity, severity, or frequency, or has delayed onset.
1. A method of treating Duchenne muscular dystrophy (DMD) comprising
administering to an individual who is suffering from or susceptible to DMD an effective amount of a recombinant follistatin protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 1 or 2 fused to an Fc domain via a peptide linker, and wherein the peptide linker comprises a sequence at least 95% identical to SEQ ID NO: 5, 6 or 7.
2. The method of claim 1 , wherein the recombinant follistatin protein comprises an amino acid sequence identical to the wild-type human follistatin protein
(SEQ ID NO: 1)
GNCWLRQAKNGRCQVLYKTELSKEECCSTGRLSTSWTEEDVNDNTLFKWM
IFNGGAPNCIPCKETCENVDCGPGKKCRMNKKNKPRCVCAPDCSNITWKG
PVCGLDGKTYRNECALLKARCKEQPELEVQYQGRCKKTCRDVFCPGSSTC
VVDQTNNAYCVTCNRICPEPASSEQYLCGNDGVTYSSACHLRKATCLLGR
SIGLAYEGKCIKAKSCEDIQCTGGKKCLWDFKVGRGRCSLCDELCPDSKS
DEPVCASDNATYASECAMKEAACSSGVLLEVKHSGSCNSISEDTEEEEED
EDQDYSFPISSILEW.
3. The method of claim 1 , wherein the recombinant follistatin protein comprises one or more deletions, mutations or insertions as compared to the wild-type human follistatin protein.
4. The method of claim 3 , wherein the recombinant follistatin protein comprises a deletion of amino acids residues 212-288 of SEQ ID NO:1.
5. The method of claim 1 , wherein the recombinant follistatin protein comprises an amino acid sequence identical to
(SEQ ID NO: 2)
GNCWLRQAKNGRCQVLYKTELSKEECCSTGRLSTSWTEEDVNDNTLFKWM
IFNGGAPNCIPCKETCENVDCGPGKKCRMNKKNKPRCVCAPDCSNITWKG
PVCGLDGKTYRNECALLKARCKEQPELEVQYQGRCKKTCRDVFCPGSSTC
VVDQTNNAYCVTCNRICPEPASSEQYLCGNDGVTYSSACHLRKATCLLGR
SIGLAYEGKCISISEDTEEEEEDEDQDYSFPISSILEW.
6. The method of claim 1 , wherein the Fc domain comprises an amino acid sequence at least 95% identical to
(SEQ ID NO: 3)
EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN
GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL
TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.
7. The method of claim 1 , wherein the recombinant follistatin protein is produced from mammalian cells.
8. The method of claim 1 , wherein the recombinant follistatin protein is administered systemically.
9. The method of claim 1 , wherein the administration of the recombinant follistatin protein results in muscle regeneration, increased muscle strength, increased flexibility, increased range of motion, increased stamina, reduced fatigability, increased blood flow, improved cognition, improved pulmonary function, inflammation inhibition, reduced muscle fibrosis, and/or reduced muscle necrosis.
10. The method of claim 1 , wherein the at least one symptom or feature of DMD is selected from the group consisting of muscle wasting, muscle weakness, muscle fragility, muscle necrosis, muscle fibrosis, joint contracture, skeletal deformation, cardiomyopathy, impaired swallowing, impaired bowel and bladder function, muscle ischemia, cognitive impairment, behavioral dysfunction, socialization impairment, scoliosis, and impaired respiratory function.