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.

1 .- 20 . (canceled) 
     
     
         21 . A fusion protein comprising a protein transduction domain and a functional Smad7 domain, wherein the functional domain is selected from the group consisting of amino acids 2-258 of the amino acid sequence as set forth in SEQ ID NO: 12 and amino acids 259-426 of the amino acid sequence as set forth in SEQ ID NO: 12. 
     
     
         22 . The fusion protein of  claim 21 , wherein the protein transduction domain is a variant of a Tat protein from HIV. 
     
     
         23 . The fusion protein of  claim 22 , wherein the protein transduction domain is selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 4, and SEQ ID NO: 6. 
     
     
         24 . The fusion protein of  claim 21 , wherein the fusion protein further comprises one or more of an epitope tag or a purification tag. 
     
     
         25 . The fusion protein of  claim 21 , wherein the amino acid sequence of the fusion protein is set forth in SEQ ID NO: 27. 
     
     
         26 . The fusion protein of  claim 25 , wherein the functional Smad7 domain has one or more biological activities selected from the group consisting of mediating cell migration, promoting cell proliferation, reducing radiation-induced DNA damage, and blocking fibrotic response. 
     
     
         27 . The fusion protein of  claim 21 , wherein the amino acid sequence of the fusion protein is set forth in SEQ ID NO: 25. 
     
     
         28 . The fusion protein of  claim 27 , wherein the functional Smad7 domain has one or more biological activities selected from the group consisting of reducing or eliminating phosphorylation of Smad2, reducing or eliminating nuclear translocation of NFκB p50 subunit, increasing cell proliferation, increasing epithelial migration, reducing apoptosis, reducing radiation-induced DNA damage, reducing inflammation, reducing angiogenesis, promoting healing in oral mucositis, promoting wound healing, and treating auto-immune disease. 
     
     
         29 . A nucleic acid molecule encoding a fusion protein comprising a protein transduction domain and a functional Smad7 domain, wherein the functional domain is selected from the group consisting of amino acids 2-258 of the amino acid sequence as set forth in SEQ ID NO: 12 and amino acids 259-426 of the amino acid sequence as set forth in SEQ ID NO: 12. 
     
     
         30 . The nucleic acid molecule of  claim 29 , wherein the nucleic acid molecule is codon-optimized for expression in one or more of bacteria or yeast. 
     
     
         31 . The nucleic acid molecule of  claim 29 , wherein the nucleic acid molecule is selected from the group consisting of SEQ ID NOs: 26, 32. 
     
     
         32 . The nucleic acid molecule of  claim 29 , wherein the nucleic acid molecule is selected from the group consisting of SEQ ID NOs: 24, 33, 34. 
     
     
         33 . The nucleic acid molecule of  claim 29 , wherein the protein transduction domain is a variant of a Tat protein from HIV. 
     
     
         34 . The nucleic acid molecule of  claim 33 , wherein the nucleic acid sequence encoding the Tat protein from HIV is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, and SEQ ID NO: 7. 
     
     
         35 . A method for preventing or treating an inflammatory disease or disorder in a subject, comprising providing to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a fusion protein comprising a protein transduction domain and a functional Smad7 domain, wherein the functional domain is selected from the group consisting of amino acids 2-258 of the amino acid sequence as set forth in SEQ ID NO: 12 and amino acids 259-426 of the amino acid sequence as set forth in SEQ ID NO: 12. 
     
     
         36 . The method of  claim 35 , wherein the inflammatory disease or disorder is selected from the group consisting of wound healing, auto-immune disease, psoriasis, oral mucositis, fibrosis, and radiation-induced tissue damage.