PARS inhibitor for cardiac allotransplantation

免疫介导的排斥反应是心脏移植治疗终末期心力衰竭的主要障碍。目前的免疫抑制方案具有有限的功效并且与实质性毒性相关。最近发现的炎症损伤机制，“聚（ADP-核糖）合成酶（PARS）途径”，现在已经涉及同种异体移植排斥反应的发病机制。PARS由过氧亚硝酸盐诱导的DNA单链断裂触发，催化ADP-核糖的能量消耗聚合，导致NAD耗尽，抑制糖酵解和线粒体呼吸，并最终减少细胞内高能磷酸盐。PARS活化还强烈上调转录因子AP-1和AP-1依赖性基因（包括ICAM-1）的转录表达。在这个提议中，我们提出了实验证据，表明药物抑制PARS活性具有有效的抗炎作用和延长心脏移植物存活。本提案的具体目的是确定PJ-34（一种新型、无毒且高效的PARS抑制剂）在心脏移植排斥的实验啮齿动物模型中预防器官功能障碍和细胞损伤的益处。PJ-34预防组织损伤和同种异体移植物存活的证明将代表在设计新的抗炎方案以延长同种异体移植物存活方面的突破。拟议的商业应用：一种新的、有效的心脏移植物排斥治疗的国内标志物估计每年价值1亿美元。全球市场估计为4亿美元。目前市场进入者如环孢菌素A和FK 506具有相当大的毒性。SBIR第一和第二阶段的资金将允许在4年内进入市场。

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.