Inhibition of pulmonary fibrosis with nutlin-3a and peptides

Abstract

In fibrotic lung fibroblasts, basal levels of p53 protein (and miR-34a) are markedly suppressed, leading to reduced p53-mediated inhibition of uPA and uPAR, or concurrent induction of PAI-1. These changes contribute to excessive FL-fibroblast proliferation and production of extracellular matrix (ECM), and, therefore, pulmonary fibrosis. These processes are reversed by treating the cells, and treating subjects suffering from idiopathic pulmonary fibrosis (IPF) with the small organic molecule nutlin-3a (NTL) or with a peptide, CSP-4 (SEQ ID NO:1), or variants or derivatives or multimers of this peptide, which increase p53 levels by inhibiting MDM2-mediated degradation of p53 protein. Use of these compounds serves as a new approach to the treatment of IPF, as they restore p53 expression and p53-mediated changes in the uPA-fibrinolytic system in FL-fibroblasts and restrict production and deposition of ECM.

What is claimed is: 
     
         1 . A composition comprising a polypeptide consisting of:
 a) amino acid sequence FTTFTVT (SEQ ID NO: 1), and at least one D-amino acid at one or both ends of the polypeptide, and 1 to 5 additional residues at one or both ends of FTTFTVT (SEQ ID NO: 1), and optionally a cap at the N-terminus, C-terminus, or both the N-terminus and C-terminus of the polypeptide; or   b) amino acid sequence FTTFTVT (SEQ ID NO: 1), and 1 to 5 additional residues at one or both ends of FTTFTVT (SEQ ID NO: 1), optionally at least one D-amino acid at one or both ends of the polypeptide, and a cap at the N-terminus, C-terminus, or both the N-terminus and C-terminus of the polypeptide;   and a pharmaceutically acceptable carrier.   
     
     
         2 . The composition of  claim 1 , wherein the 1 to 5 additional residues include a KAS sequence at the N-terminal end of FTTFTVT (SEQ ID NO: 1). 
     
     
         3 . The composition of  claim 1 , wherein the 1 to 5 additional residues include a K at the C-terminal end of FTTFTVT (SEQ ID NO: 1). 
     
     
         4 . The composition of  claim 1 , wherein the cap is present at the N-terminus of the polypeptide and is an acyl or amido group. 
     
     
         5 . The composition of  claim 1 , wherein the cap is present at the C-terminus of the polypeptide and is an acyl or amido group. 
     
     
         6 . The composition of  claim 1 , wherein the polypeptide consists of:
 amino acid sequence FTTFTVT (SEQ ID NO: 1), and at least one D-amino acid at one or both ends of the polypeptide, and 1 to 5 additional residues at one or both ends of FTTFTVT (SEQ ID NO: 1), and optionally a cap at the N-terminus, C-terminus, or both the N-terminus and C-terminus of the polypeptide.   
     
     
         7 . The composition of  claim 1 , wherein the polypeptide consists of:
 amino acid sequence FTTFTVT (SEQ ID NO: 1), and at least one D-amino acid at one or both ends of the polypeptide, and 1 to 5 additional residues at one or both ends of FTTFTVT (SEQ ID NO: 1), and a cap at the N-terminus, C-terminus, or both the N-terminus and C-terminus of the polypeptide.   
     
     
         8 . The composition of  claim 1 , wherein the polypeptide consists of amino acid sequence FTTFTVT (SEQ ID NO: 1), and 1 to 5 additional residues at one or both ends of FTTFTVT (SEQ ID NO: 1), and a cap at the N-terminus, C-terminus, or both the N-terminus and C-terminus of the polypeptide. 
     
     
         9 . A method of treating a subject having a disease or condition characterized by fibrosis, the method comprising administering the composition of  claim 1  to the subject. 
     
     
         10 . The method of  claim 9 , wherein the composition is administered intranasally, intrabronchially, intrapleurally or by instillation into lungs of the subject. 
     
     
         11 . The method of  claim 9 , wherein the fibrosis is pulmonary fibrosis. 
     
     
         12 . The method of  claim 9 , wherein the fibrosis is idiopathic pulmonary fibrosis. 
     
     
         13 . The method of  claim 9 , wherein the composition is administered by instillation into the lungs of the subject. 
     
     
         14 . The method of  claim 9 , wherein the composition reduces fibrosis in the subject. 
     
     
         15 . A method of increasing p53 and/or plasminogen activator inhibitor-1 (PAI-1) levels in a subject, comprising administering the composition of  claim 1  to the subject. 
     
     
         16 . The method of  claim 15 , wherein the subject has an acute lung injury or a fibrotic condition. 
     
     
         17 . The method of  claim 15 , wherein the composition is administered by oral, parenteral, topical, transdermal, intravaginal, intrapenile, intranasal, intrabronchial, intracranial, intraocular, intraaural or rectal administration. 
     
     
         18 . The method of  claim 15 , wherein the composition is administered intranasaly, intrabronchially, or by instillation into lungs of the subject. 
     
     
         19 . The method of  claim 15 , wherein the composition administered by injection. 
     
     
         20 . The method of  claim 15 , wherein the pharmaceutical composition is administered systemically. 
     
     
         21 . The method of  claim 15 , wherein the subject has an acute lung injury. 
     
     
         22 . The method of  claim 15 , wherein the subject has a fibrotic condition. 
     
     
         23 . The method of  claim 22 , wherein the fibrotic condition comprises pulmonary fibrosis. 
     
     
         24 . The method of  claim 15 , wherein the subject has idiopathic pulmonary fibrosis.