Prevention of graft rejection by catalytic antioxidants

DESCRIPTION (provided by the applicant): Transplantation represents the only therapy for end-stage organ failure caused by a variety of incurable diseases. However, rejection by the host represents a major obstacle to long-term survival of transplants. While acute rejection is currently controlled by immunosuppressive drugs, continuous treatment with these non-selective agents impairs the entire immune system thereby increasing the risk for infections and cancer in patients. In addition, many of these drugs exhibit long-term toxic effects. Most importantly, a large proportion of solid organ transplants succumb to chronic rejection, a phenomenon associated with fibrosis, and vasculopathy. At present time, there is no treatment for chronic rejection. These observations underscore the need for novel therapies in transplantation. Eukarion Inc. has developed a class of low molecular weight molecules that are catalytic reactive oxygen species scavengers, acting as mimics for the endogenous antioxidant enzymes, superoxide dismutase and catalase. These compounds have demonstrated efficacy in 3 of the main events associated with tranplant rejection" i) tissue damage due to anoxia, ii) ischemia/reperfusion injury and iii) inflammation. Most importantly, we have shown that one of these compounds can delay the acute rejection of skin grafts in mice. Based on these observations we intend to develop a series a compounds with greater lipophilicity and in vivo half-life to be tested in the prevention of acute and/or chronic rejection of solid organ transplants for further development. To achieve this, we propose the following specific aims: 1) To synthesize and evaluate a series of analogs with greater potency or efficacy, i.e., a series with enhanced lipophilicity and improved in vivo half-life. 2) To test the effect of selected EUK compounds on anti-donor inflammatory immune response and on the rejection of heart allotransplants in mice.