TGF-Beta Antagonists for Accelerating Wound Healing

DESCRIPTION (provided by applicant): Impaired or abnormal wound healing is a major health problem for elderly, diabetic, immunosuppressed, immobilized, burn-injured and keloid individuals. Every year in the United States, 6.5 million people have chronic skin ulcers caused by pressure, venous stasis or diabetes mellitus, more than 1.25 million people suffer from burns and 0.25 million people have keloids sufficiently severe to require surgery. Currently, there are no effective wound healing-promoting agents available for treating these disorders. The current cost of the treatment and care of the healing-impaired disorders is estimated to be $ ~ 20 billion per year in the United States. It is projected to increase at least 10 % annually. Recent genetic evidence revealed that TGF-a or TGF-a-induced cellular signaling may provide the best targets for developing effective wound healing- promoting agents. We recently found that synthetic TGF-a peptide antagonists (we have termed TGF-a peptantagonists) developed in our laboratory, which block TGF-a binding to TGF-a receptors and prevent TGF-a-induced growth inhibition in epithelial cells and TGF-a-stimulated extracellular matrix biosynthesis in fibroblasts, accelerate wound healing and reduce scarring in animal skin burn/excision wound models. We hypothesize that TGF-a peptantagonists will be effective wound healing-promoting agents in humans. The goal of this proposal is to generate new chemical forms of TGF-a peptantagonists with improved solubility, increased efficacy and suitability for both topical application and injection. These studies should generate TGF-a peptantagonist drug candidates for Phase II studies. It is our hope that these studies will lead to the generation of robust wound healing-promoting agents for human use.