Grant: Proof of Principle Program - Phase I

Fibrosis seen in different organs such as skin, liver, lung, kidney and arteries is a serious pathologic disorder in which the properties of normal tissue are disturbed due to an alteration in the extracellular matrix (ECM) composition and organization. Skin fibrosis such as hypertrophic scarring and keloid are frequently seen following trauma, thermal injuries and surgical incisions. They are clinically raised, firm, red, itchy, bulky and inelastic quality and limit the mobility of joints and extremities. Current treatment modalities for this devastating condition still remain unsatisfactory. For example, neither pressure garment therapy, intralesional injections of corticosteroids and interferon nor surgical revision is effective. We recently found that tryptophan metabolites namely kynurenine (Kyn) and Kyn. acid reduces the accumulation of ECM in cell culture and in an animal fibrotic model. The therapeutic use of Kyn and its metabolites for treatment of fibrosis is very attractive because: 1) They are small molecules and would penetrate the dermal barrier to reach skin where they modulate the expression of matrix by dermal fibroblasts, 2) They are easy to either purchase or manufacture, 3) They are stable when kept at 4oC and room temperature up to 30 days examined and 4) The cost of these metabolites are relatively low. Here we propose that Kyn and KynA can safely be delivered to fibrotic site where they improve and /or prevent fibrotic conditions without compromising the health of the patients . Thus, prior to conducting any clinical trial, there is a need to evaluate: 1) The effective time and dose of KynA in improving and /or preventing rabbit ear fibrotic condition, 2) The safety/cytotoxicity of KynA in skin cells as well as in open and closed wounds in guinea pigs, 3) The efficacy of new formulation of these medications in fibrotic animal model and 4) The anti-fibrotic effects of new chemicals with structural similarity to KynA.