Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition

Abstract

The described invention provides compositions and methods for preventing or treating a disease, condition, or pathologic process characterized by aberrant fibroblast proliferation and extracellular matrix deposition in a tissue of a subject. The method includes administering a therapeutic amount of a pharmaceutical composition comprising a polypeptide having the amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or functional equivalent thereof, and a pharmaceutically acceptable carrier.

1 . A method for treating a disease, condition, or process characterized by aberrant fibroblast proliferation and extracellular matrix deposition in a lung of a subject selected from an acute lung injury (ALI), acute respiratory distress syndrome (ARDS), radiation-induced fibrosis or transplant rejection, the method comprising:
 administering to the subject a pharmaceutical composition comprising a therapeutic amount of a polypeptide of the amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof selected from the group consisting of a polypeptide of amino acid sequence FAKLAARLYRKALAROLGVAA (SEQ ID NO: 3); a polypeptide of amino acid sequence KAFAKLAARLYRKALAROLGVAA (SEQ ID NO: 4); and a polypeptide of amino acid sequence HRRIKAWLKKIKALARQLGVAA (SEQ ID NO: 7), and a pharmaceutically acceptable carrier thereof,   wherein the therapeutic amount is effective to reduce the fibroblast proliferation and extracellular matrix deposition in the tissue of the subject.   
     
     
         2 .- 8 . (canceled) 
     
     
         9 . The method according to  claim 1 , wherein the acute lung injury to lung tissue is caused by administration of bleomycin. 
     
     
         10 . The method according to  claim 1 , wherein acute lung injury to lung tissue results from an allergic reaction, an autoimmune reaction, inhalation of environmental particulates, a bacterial infection, a viral infection, mechanical damage to a lung of the subject, or a combination thereof. 
     
     
         11 . The method according to  claim 1 , wherein the acute lung injury (ALI), acute respiratory distress syndrome (ARDS), radiation-induced fibrosis or transplant rejection is further characterized by an inflammation in the tissue. 
     
     
         12 . The method according to  claim 11 , wherein the inflammation is an acute or a chronic inflammation. 
     
     
         13 . The method according to  claim 11 , wherein the inflammation is mediated by at least one cytokine selected from the group consisting of Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and Interleukin-1β (IL-1β). 
     
     
         14 . The method according to  claim 1 , wherein the aberrant fibroblast proliferation and collagen deposition in the tissue is characterized by an aberrant activity of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) in the tissue compared to the activity of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) in the tissue of a normal healthy control subject. 
     
     
         15 . (canceled) 
     
     
         16 . The method according to  claim 1 , wherein the step of administering occurs parenterally or by inhalation. 
     
     
         17 . (canceled) 
     
     
         18 . The method according to  claim 1 , wherein the step of administering occurs at one time as a single dose. 
     
     
         19 . The method according to  claim 1 , wherein the step of administering is performed as a plurality of doses over a period of time. 
     
     
         20 . The method according to  claim 19 , wherein the period of time is a day, a week, a month, a month, a year, or multiples thereof. 
     
     
         21 . The method according to  claim 1 , wherein the step of administering is performed at least once monthly, at least once weekly, or at least one daily. 
     
     
         22 . The method according to  claim 1 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent. 
     
     
         23 . The method according to  claim 22 , wherein the additional therapeutic agent is selected from the group consisting of a purified bovine Type V collagen, an IL-13 receptor antagonist, a protein tyrosine kinase inhibitor, an endothelial receptor antagonist, a dual endothelin receptor antagonist, a prostacyclin analog, an anti-CTGF monoclonal antibody, an endothelin receptor antagonist (A-selective), AB0024, a lysyl oxidase-like 2 (LOXL2) monoclonal antibody, a c-Jun kinase (JNK) inhibitor, pirfenidone, IFN-γ1b, a pan-neutralizing IgG4 human antibody against all three TGF-β isoforms, a recombinant human pantraxin-2 protein (rhPTX-2), a bispecific IL-4/IL-13 antibody, a humanized monoclonal antibody targeting integrin αvβ6, N-acetylcysteine, sildenafil, a Tumor Necrosis Factor (TNF) antagonist (etanercept), and a combination thereof. 
     
     
         24 . The method according to  claim 22 , wherein the additional therapeutic agent is a glucocorticoid selected from the group consisting of prednisone, budesonide, and mometasone furoate, and a combination thereof. 
     
     
         25 . The method according to  claim 22 , wherein the additional therapeutic agent is a bronchodilator selected from the group consisting of a leukotriene modifier, an anticholinergic bronchodilator, a short-acting β2-agonist, and long-acting β2-agonist, and a combination thereof. 
     
     
         26 . The method according to  claim 22 , wherein the additional therapeutic agent is an analgesic agent. 
     
     
         27 . The method according to  claim 22 , wherein the additional therapeutic agent is an anti-infective agent. 
     
     
         28 . (canceled) 
     
     
         29 . The method according to  claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence FAKLAARLYRKALARQLGVAA (SEQ ID NO: 3). 
     
     
         30 . The method according to  claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence KAFAKLAARLYRKALARQLGVAA (SEQ ID NO: 4). 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . The method according to  claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence HRRIKAWLKKIKALARQLGVAA (SEQ ID NO: 7). 
     
     
         34 .- 49 . (canceled) 
     
     
         50 . The method according to  claim 1 , wherein the carrier is selected from the group consisting of a controlled release carrier, a delayed release carrier, a sustained release carrier, and a long-term release carrier. 
     
     
         51 . The method according to  claim 1 , wherein the pharmaceutical composition is in a form of a dry powder. 
     
     
         52 . The method according to  claim 51 , wherein the dry powder comprises microparticles with Mass Median Aerodynamic Diameter (MMAD) of 1 to 5 microns. 
     
     
         53 . The method according to  claim 1 , wherein the therapeutic amount of the pharmaceutical composition is administered via an inhalation device. 
     
     
         54 . The method according to  claim 53 , wherein the inhalation device is a nebulizer. 
     
     
         55 . The method according to  claim 53 , wherein the inhalation device is a metered-dose inhaler (MDI). 
     
     
         56 . The method according to  claim 53 , wherein the inhalation device is a dry powder inhaler (DPI). 
     
     
         57 . The method according to  claim 53 , wherein the inhalation device is a dry powder nebulizer.