Inhibition of corneal graft rejection by antioxidants

DESCRIPTION (provided by applicant): Corneal transplantation is the most common form of tissue allotransplantation (47,000 cases per year). However, 15% of the grafts are rejected within a year in "high risk" patients. In "low risk" patients, immunosuppressive drug treatment is associated with induction of cataracts, glaucoma and infections. In fact, despite the high rate of success, more corneal allografts rejections fail per year in the United States than any other form of solid-tissue transplant. It is therefore necessary to develop new treatments to prevent high-risk corneal graft and to avoid utilization of immunosuppressive agents in all patients. Eukarion has developed a series of synthetic mimetics of the antioxidant enzymes superoxide dismutase and catalase. These compounds have been shown to promote tissue preservation and to block deleterious immune responses in a number of animal models. Particularly, they prevent autoimmune diseases and skin graft rejection without widespread immunosuppression and toxicity. Furthermore, they show protective effect in various topical applications. Eukarion compounds have been shown to be efficacious in 3 processes leading to corneal graft rejection e.g: i) preservation of tissue before transplantation, ii) corneal neovascularization, iii) inflammation/immune rejection. Here, we propose to test the effect of these compounds on corneal graft rejection following ex vivo treatment of the graft and/or topical treatment of recipient. We plan: 1) to synthetize and screen analogs of these compounds for their cellular permeability and stability. 2) to test selected compounds for their ability to prevent/retard allogenic corneal transplantation. We will identify a lead molecule for topical treatment delaying/preventing corneal allograft rejection for further development. This will hopefully provide the therapeutic community with a molecule that would be efficacious in acute corneal transplant rejection without the side effects associated with current therapies.