Regenerative polypeptides and uses thereof

Abstract

Described herein are polypeptides comprising an FGF17, IGF2, or BMP7 amino acid sequence and an amino acid sequence from a heterologous polypeptide useful for the treatment of soft-tissue and muscle diseases, disorders, and injuries. Also described herein are synergistic combinations of a Fibroblast Growth Factor Receptor agonist and a glycosaminoglycan, an Insulin-like Growth Factor 1 Receptor (IGF1R) agonist and a short chain fatty acid, and BMP receptor agonists and mTOR activators and/or glycosaminoglycans. Also described are methods of treating muscle and soft-tissue diseases comprising administering the polypeptides and/or synergistic compositions.

What is claimed is: 
     
         1 . A fusion protein, comprising:
 a human serum albumin (HSA) polypeptide covalently coupled to an insulin-like growth factor 2 (IGF2) polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO: 76.   
     
     
         2 . The fusion protein of  claim 1 , wherein the HSA polypeptide comprises an amino acid sequence at least 90% identical to SEQ ID NO: 109. 
     
     
         3 . The fusion protein of  claim 1 , wherein the HSA polypeptide comprises the amino acid sequence of SEQ ID NO: 109. 
     
     
         4 . The fusion protein of  claim 1 , wherein the IGF2 polypeptide consists of an amino acid sequence that is at least 90% identical to SEQ ID NO: 76. 
     
     
         5 . The fusion protein of  claim 1 , wherein the IGF2 polypeptide amino acid sequence is at least 98% identical to SEQ ID NO: 76. 
     
     
         6 . The fusion protein of  claim 5 , wherein the IGF2 polypeptide consists of an amino acid sequence that is at least 98% identical to SEQ ID NO: 76. 
     
     
         7 . The fusion protein of  claim 1 , wherein the HSA polypeptide is fused to the IGF2 polypeptide at the N-terminus of the IGF2 polypeptide sequence. 
     
     
         8 . The fusion protein of  claim 1 , wherein the HSA polypeptide is fused to the IGF2 polypeptide at the C-terminus of the IGF2 polypeptide sequence. 
     
     
         9 . The fusion protein of  claim 1 , wherein a peptide linker separates the HSA polypeptide and the IGF2 polypeptide in the fusion protein. 
     
     
         10 . The fusion protein of  claim 9 , wherein the peptide linker is covalently coupled to the C-terminus of the HSA polypeptide and to the N-terminus of the IGF2 polypeptide. 
     
     
         11 . The fusion protein of  claim 9 , wherein the peptide linker is covalently coupled to the C-terminus of the IGF2 polypeptide and to the N-terminus of the HSA polypeptide. 
     
     
         12 . The fusion protein of  claim 9 , wherein the peptide linker comprises a flexible peptide linker. 
     
     
         13 . The fusion protein of  claim 12 , wherein the flexible peptide linker comprises a glycine-rich linker. 
     
     
         14 . The fusion protein of  claim 13 , wherein the glycine-rich linker comprises a glycine-serine linker. 
     
     
         15 . The fusion protein of  claim 14 , wherein the glycine-serine linker comprises a multimer of the sequence GGGGS(n), wherein n is 1-5. 
     
     
         16 . The fusion protein of  claim 14 , wherein the glycine-serine linker comprises the amino acid sequence of SEQ ID NO: 104. 
     
     
         17 . A fusion protein, comprising:
 a human serum albumin (HSA) polypeptide covalently coupled to an insulin-like growth factor 2 (IGF2) polypeptide comprising an N-terminal deletion or a C-terminal deletion.   
     
     
         18 . The fusion protein of  claim 17 , wherein the IGF2 polypeptide comprises the N-terminal deletion and the C-terminal deletion. 
     
     
         19 . A pharmaceutical composition comprising:
 a fusion protein comprising:
 i. a human serum albumin (HSA) polypeptide, 
 ii. an insulin-like growth factor 2 (IGF2) polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO: 76, and 
 iii. a peptide linker covalently coupled to the HSA polypeptide and to the IGF2 polypeptide; and 
   a pharmaceutically acceptable excipient, carrier, or diluent.