Ptd-smad7 therapeutics

Abstract

The present technology provides methods and compositions for the treatment of inflammatory and/or tissue damage conditions. In particular, the use of Smad7 compositions delivered locally or systemically to a site of inflammation and/or tissue damage is described. Other specific embodiments concern treatment or prevention of side effects caused by radiation and/or chemotherapy, including but not limited to oral and gastric mucositis. Also provided are codon-optimized nucleic acids encoding for Smad7 fusion proteins.

What is claimed is: 
     
         1 . A purified polypeptide comprising a protein transduction domain and a human mothers against decapentaplegic-7 protein (Smad7) fragment comprising amino acids 259-426 of the human Smad7 protein, wherein the Smad7 fragment retains one or more biological activities of the functional full-length Smad7 protein, wherein the purified polypeptide translocates to the nucleus of a cell, and wherein the polypeptide lacks at least amino acids 1-203 of the human Smad7 protein. 
     
     
         2 . The polypeptide of  claim 1 , wherein the human Smad7 fragment consists of amino acids 259-426 of the human Smad7 protein. 
     
     
         3 . The polypeptide of  claim 1 , wherein the protein transduction domain is Tat. 
     
     
         4 . The polypeptide of  claim 2 , wherein the protein transduction domain is Tat. 
     
     
         5 . The polypeptide of  claim 1 , wherein the polypeptide is an isolated polypeptide. 
     
     
         6 . The polypeptide of  claim 1 , wherein the purified polypeptide is free of other proteins. 
     
     
         7 . The polypeptide of  claim 1 , wherein purified polypeptide is at least 80% purified. 
     
     
         8 . The polypeptide of  claim 1 , wherein the polypeptide lacks at least amino acids 1-250 of the human Smad7 protein. 
     
     
         9 . The polypeptide of  claim 1 , further comprising one or more linkers connecting the at least one protein transduction domain to the polypeptide comprising amino acids 259-426 of the human Smad7 protein. 
     
     
         10 . A pharmaceutical composition comprising the polypeptide-of  claim 1 , and one or more pharmaceutically acceptable excipients. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition is formulated for oral, subcutaneous, intravenous, intranasal, buccal, urethral, rectal, vaginal, mucosal, intradermal, or topical administration. 
     
     
         12 . A method for treating an inflammatory condition in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of  claim 5 . 
     
     
         13 . The method of  claim 12 , wherein the inflammatory condition is selected from the group consisting of radiation-induced damage, psoriasis, stomatitis, proctitis, ulcerative colitis, Crohn's disease, irritable bowel disease, and inflammatory bowel disease. 
     
     
         14 . A method for treating a disease or disorder in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of  claim 10 , wherein the administration of the-pharmaceutical composition results in an increase in one or more of cell proliferation or cell migration, or reducing one or more of apoptosis or DNA damage in the subject. 
     
     
         15 . A method for treating a disease or disorder in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of  claim 10 , wherein the disease or disorder is selected from the group consisting of chronic and acute wounds, inflammatory diseases and inflammatory disorders, aberrant healing, auto-immune diseases and auto-immune disorders and a combination thereof. 
     
     
         16 . The method of  claim 15 , wherein treating chronic and acute wounds comprises promoting wound healing of the chronic wounds, acute wounds, or a combination thereof. 
     
     
         17 . The method of  claim 15 , wherein the chronic wounds are selected from the group consisting of diabetic ulcers, pressure ulcers, venous ulcers, mucositis, and oral ulcers. 
     
     
         18 . The method of  claim 15 , wherein the acute wounds are selected from the group consisting of trauma-induced wounds, surgical wounds, and acute wounds that induce scarring. 
     
     
         19 . A construct comprising a nucleotide sequence encoding a polypeptide comprising amino acids 259-426 of the human Smad7 protein represented by SEQ ID NO: 12 and the nucleotide sequence does not encode amino acids 1-203 of the human Smad7 protein further comprising at least one protein transduction domain. 
     
     
         20 . The construct of  claim 19 , wherein the nucleotide sequence comprises SEQ NOs: 24, 25, 26 or 93. 
     
     
         21 . (canceled)