Peptide Antagonists of TGF-Beta Family Members and Therapeutic Uses Thereof

Abstract

This invention is drawn to methods of using peptide-based antagonists of TGF-beta to facilitate the healing of cutaneous wounds that includes burns, lacerations and scrapes. The administration of peptide TGF-beta antagonists to wounds results in reduced scarring, wound contraction and deposition of extracellular matrix components, and increased rates of reepithelialization during wound healing.

1 . A non-naturally occurring peptide derived from residues 41 to 65 of TGF-β, wherein said non-naturally occurring peptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:4 and contains the sequence WSXD wherein X is any amino, acid. 
     
     
         2 . The peptide of  claim 1 , wherein said non-naturally occurring peptide comprises an amino acid sequence wherein the amino acid residues corresponding to cysteine residues 44 and 48 of TGF-β are replaced by serine residues. 
     
     
         3 . The peptide of  claim 1 , wherein said peptide is conjugated to a carrier protein. 
     
     
         4 . The peptide of  claim 3 , wherein said carrier protein is bovine serum albumin or human carbonic anhydrase. 
     
     
         5 . The peptide of  claim 1 , wherein said peptide is conjugated to a synthetic polymer. 
     
     
         6 . The peptide of  claim 5 , wherein said synthetic polymer is polyethylene glycol. 
     
     
         7 . The peptide of  claim 1 , wherein said peptide is radiolabeled. 
     
     
         8 . The peptide of  claim 7 , wherein said peptide is radiolabeled with  125 I. 
     
     
         9 . The peptide of  claim 1 , wherein said WSXD sequence is in the middle of the peptide amino acid sequence. 
     
     
         10 . The peptide of  claim 1 , wherein said peptide comprises the amino acid sequence of SEQ ID NO:12. 
     
     
         11 . A method for inhibiting TGF-β activity in a mammal or mammalian cell, comprising the steps of:
 a) administering to said mammal or mammalian cell a composition comprising a non-naturally occurring peptide derived from residues 41 to 65 of TGF-β, wherein said non-naturally occurring peptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:4 and contains the sequence WSXD wherein X is any amino acid; and 
 b) inhibiting the binding of TGF-β to the TGF-β receptor, thereby inhibiting the activity of TGF-β in said mammal or mammalian cell. 
 
     
     
         12 . The method of  claim 11  wherein said non-naturally occurring peptide comprises an amino acid sequence wherein the amino acid residues corresponding to cysteine residues 44 and 48 of TGF-β are replaced by serine residues. 
     
     
         13 . The method of  claim 11 , wherein said peptide is conjugated to a carrier protein. 
     
     
         14 . The method of  claim 13 , wherein said carrier protein is bovine serum albumin or human carbonic anhydrase. 
     
     
         15 . The method of  claim 11 , wherein said peptide is conjugated to a synthetic polymer. 
     
     
         16 . The method of  claim 15 , wherein said synthetic polymer is polyethylene glycol. 
     
     
         17 . The method of  claim 11 , wherein said peptide is radiolabeled. 
     
     
         18 . The method of  claim 17 , wherein said peptide is radiolabeled with  125 I. 
     
     
         19 . The method of  claim 11 , wherein said WSXD sequence is in the middle of the peptide amino acid sequence. 
     
     
         20 . The method of  claim 11 , wherein said mammal is a human or wherein said mammalian cell is a human cell. 
     
     
         21 . A method for treating a disease mediated by TGF-β activity in a mammal, comprising the steps of:
 a) administering to said mammal a composition comprising a non-naturally occurring peptide derived from residues 41 to 65 of TGF-β, wherein said non-naturally occurring peptide comprises an amino acid sequence that is at least 90% identical to SEQ IDl NO:4 and contains the sequence WSXD wherein X is any amino acid; and 
 b) inhibiting the binding of TGF-β to the TGF-β receptor, thereby treating a disease mediated by TGF-β in said mammal or mammalian cell. 
 
     
     
         22 . The method of  claim 21 , wherein said non-naturally occurring peptide comprises an amino acid sequence wherein the amino acid residues corresponding to cysteine residues 44 and 48 of TGF-β are replaced by serine residues. 
     
     
         23 . The method of  claim 21 , wherein said peptide is conjugated to a carrier protein. 
     
     
         24 . The method of  claim 23 , wherein said carrier protein is bovine serum albumin or human carbonic anhydrase. 
     
     
         25 . The method of  claim 21 , wherein said peptide is conjugated to a synthetic polymer. 
     
     
         26 . The method of  claim 25 , wherein said synthetic polymer is polyethylene glycol. 
     
     
         27 . The method of  claim 21 , wherein said WSXD sequence is in the middle of the peptide amino acid sequence. 
     
     
         28 . The method of  claim 21 , wherein said mammal is a human. 
     
     
         29 . The method of  claim 21 , wherein said disease is selected from the group consisting of scarring of a wound, lung injury in adult respiratory distress syndrome (ARDS), restenosis following angioplasty, intimal hyperplasia following angioplasty, tissue fibrosis, and glomerulonephritis. 
     
     
         30 . The method of  claim 29  wherein said tissue fibrosis is selected from the group consisting of scar formation, liver cirrhosis, kidney fibrosis, cystic fibrosis, lung fibrosis, and heart fibrosis. 
     
     
         31 . The method of  claim 29 , wherein said wound is selected from the list consisting of a puncture wound, a laceration, an abrasion, a pressure wound and a burn.