Novel antioxidant catalyst for transplant rejection

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DESCRIPTION (provided by the applicant): Immune-mediated rejection is the principal obstacle to the use of heart transplantation for the treatment of end-stage cardiac failure. Current immunosuppressive regimens have limited efficacy and are associated with substantial toxicity. A key final common pathway of allograft injury is mediated by the free radical nitric oxide and the potent oxidant, peroxynitrite, which is formed from the reaction of nitric oxide and superoxide anion. Inotek is developing a novel class of peroxynitrite decomposition catalysts that are dramatically protective in experimental models of oxidant-mediated inflammatory diseases, including autoimmune arthritis, diabetes, and colitis. These agents are fundamentally superior to conventional anti-oxidants: First, they act as catalysts, rather than scavengers, and are therefore not consumed in the decomposition of oxidant species. Second, their reaction rate is in excess of 100 million, more than I million fold faster than classic anti-oxidants such as Vitamin C and E. Third, they have profound activity against both peroxynitrite and hydrogen peroxide, and thus provide broad-spectrum protection against oxidative and nitrosative stress. In vivo studies confirm their dramatic potency, as evidenced by protection in various models of inflammation at oral doses in the microgram per kg range. In experimental disease models, they have been shown to eliminate colitis, increase survival in endotoxic shock, and profundly reduce tissue damage during ischemia-reperfusion. The specific aim of the present proposal is to determine the benefit of our lead peroxynitrite decomposition catalyst, INO-1080, in the prevention of organ dysfunction and cellular injury in an experimental rodent model of heterotopic cardiac allograft rejection. We will establish the synergy of INO-1080, alone and with sub-therapeutic dosing of cyclosporine A. Demonstration that INO-1080 prevents tissue injury and prolongs allograft survival would represent a breakthrough in the design of novel anti-inflammatory regimens to prolong allograft survival. Phase II funding would support pharamcokinetic, toxicology, and pharmacodynamic studies required for IND submission and FDA-sanctioned clinical Phase I trials.