ADAM12 Inhibitors and Their Use Against Inflammation-Induced Fibrosis

Abstract

The present invention relates to the field of fibrosis and inflammation and more particularly to the use of ADAM12 (A Disintegrin and Metalloproteinase 12) inhibitors to prevent or treat inflammation-induced fibrosis. The present invention also relates to the use of ADAM12 as a marker for inflammation-induced fibrosis and to the ablation of ADAM12 expressing cells as therapeutic approach to interfere with the development of pro-fibrotic cells.

1 . (canceled) 
     
     
         2 . The composition according to  claim 5 , wherein the inhibitor affects or inhibits ADAM12 gene expression or ADAM12 protein activity. 
     
     
         3 . The composition according to  claim 5 , wherein the inhibitor is an antisense oligonucleotide, a siRNA, a miRNA, a small organic molecule, an enzyme, an antibody, a peptide or a polynucleotide encoding a polypeptide. 
     
     
         4 . The composition according to  claim 5 , wherein the inhibitor is a small interfering RNA specific for ADAM12. 
     
     
         5 . A composition for preventing or treating inflammation-induced fibrosis comprising an ADAM12 inhibitor and a pharmaceutically acceptable carrier. 
     
     
         6 . A method for preventing or treating inflammation-induced fibrosis in a subject, comprising the step of administering the composition as defined in  claim 5  to said subject. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . A method for diagnosing inflammation-induced fibrosis in a subject, comprising:
 detecting the expression of ADAM12 gene in stromal cells from a biological sample of said subject, and   relating the expression of ADAM12 gene to the presence or the advent of inflammation-induced fibrosis.   
     
     
         10 . A method for diagnosing inflammation-induced fibrosis in a subject, comprising:
 determining the level of ADAM12 gene expression in stromal cells from a biological sample of said subject, and   comparing this level with a reference level, whereby an increased level of ADAM12 gene expression in said stromal cells with respect to the reference level indicating the presence or the advent of inflammation-induced fibrosis.   
     
     
         11 . A method for detecting stromal cells activated upon tissue injury and inflammation and that will generate pro-fibrotic cells in a subject comprising:
 detecting the expression of ADAM12 gene in the stromal cells; and   relating the expression of ADAM12 gene to the presence of these stromal cells.   
     
     
         12 . The method according to  claim 9 , further comprising a step of isolating stromal cells, before the step of detecting. 
     
     
         13 . An isolated bacterial strain comprising a generated bacterial artificial chromosome (BAC) expressing a Cre recombinase and a fluorescent reporter EGFP under control of the Adam12 gene, deposited on Aug. 28, 2009 under No I-4225 at the CNCM. 
     
     
         14 . A transgenic mouse comprising the BAC contained in the bacterial strain according to  claim 13 . 
     
     
         15 . A screening method for identifying ADAM12 inhibitors, comprising the steps of:
 inducing an inflammation response at a desired site of the transgenic mouse of  claim 14 ,   applying at the site of inflammation a candidate compound to be tested,   evaluating expression of the fluorescent reporter EGFP polypeptide; and   identifying that the expression level of said fluorescent reporter EGFP is inhibited, therefore indicating that the candidate compound has the capacity of inhibiting ADAM12 expression.   
     
     
         16 . A cytotoxic compound able to specifically kill ADAM12 expressing stromal cells for use to prevent or treat fibrosis, wherein said compound comprises a targeting molecule selected among an antibody or a small interfering RNA specific for ADAM12 according to  claim 3 , and a cytotoxic molecule which is a toxin. 
     
     
         17 . A composition for preventing or treating inflammation-induced fibrosis comprising the cytotoxic compound of  claim 16 , and a pharmaceutically acceptable carrier. 
     
     
         18 . (canceled) 
     
     
         19 . The method according to  claim 10 , further comprising a step of isolating stromal cells, before the step of detecting. 
     
     
         20 . The method according to  claim 11 , further comprising a step of isolating stromal cells, before the step of detecting.