PARS inhibitor for cardiac allotransplantation

用于同种异体心脏移植的 PARS 抑制剂

• 批准号: 6440952
• 负责人: PRAKASH G JAGTAP
• 金额: $ 18.63万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2004-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6440952
• 关键词: antiinflammatory agents; artificial immunosuppression; drug design /synthesis /production; enzyme activity; enzyme inhibitors; free radical oxygen; heart transplantation; homologous transplantation; laboratory rat; nitric oxide; pentosyltransferase; peroxynitrites; transcription factor; transplant rejection

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.

免疫介导的排斥反应是使用心脏移植来治疗终阶段心脏衰竭的主​​要障碍。当前的免疫抑制方案的功效有限，并且与实质性毒性有关。最近发现的一种炎症性损伤机制，即“聚（ADP-核糖）合成酶（PARS）途径”，现已与同种异体移植排斥的发病机理有关。由过氧亚硝酸盐诱导的DNA单链断裂触发，PARS催化ADP-核糖的能量消耗性聚合，导致NAD消耗，抑制糖酵解和线粒体呼吸的抑制，以及最终减少细胞内高能磷酸盐。 PARS激活还强烈上调了转录因子AP-1和AP-1依赖基因的转录表达的表达，包括ICAM-1。在此提案中，我们提出了实验证据，表明药理学抑制PARS活性具有有效的抗炎作用，并延长了同种异体移植的存活率。本提案的具体目的是确定PJ-34的益处，PJ-34是一种新型，无毒且高度有效的PAR抑制剂，在预防器官功能障碍和细胞损伤中，在心脏移植排斥的实验啮齿动物模型中。证明PJ-34可防止组织损伤并延长移植物的存活，这将代表新型抗炎性方案的设计，以延长同种异体移植的存活。拟议的商业应用：一种新颖的，有效的心脏同种异体移植抑制疗法的国内标记估计为每年1亿美元。全球市场估计为4亿美元。当前的市场进入者（例如环孢素A和FK506）具有实质性的毒性。 SBIR阶段I和II阶段的资金将在4年内进入市场。