PARS inhibitor for cardiac allotransplantation

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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 recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) Pathway", has now been implicated in the pathogenesis of allograft rejection. Triggered by peroxynitrite-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates. PARS activation also strongly up-regulates expression of the transcription expression of the transcription factor AP-1 and AP-1 dependent genes, including ICAM-1. In this proposal, we present experimental evidence that pharmacologic inhibition of PARS activity has potent anti-inflammatory effects and prolongs cardiac allograft survival. The specific aim of the present proposal has to determine the benefit of PJ-34, a novel, non-toxic, and highly potent PARS inhibitor, in the prevention of organ dysfunction and cellular injury in an experimental rodent model of cardiac transplant rejection. Demonstration that PJ-34 prevents tissue injury and prolongs graft survival would represent a breakthrough in the design of novel anti- inflammatory regimens to prolong allograft survival. PROPOSED COMMERCIAL APPLICATIONS: The domestic marker for a novel, effective therapy for cardiac allograft rejection is estimated at $100 million per annum. Global markets are estimated at $400 million. Current market entrants such as cyclosporine A and FK506, have substantial toxicity. Funding of SBIR Phases I and II would allow for market entry in 4 years.