PARS INHIBITOR FOR ISLET CELL TRANSPLANT REJECTION

炎症和排斥反应是胰岛细胞移植治疗胰岛素依赖型糖尿病的主要障碍。目前的治疗方案疗效有限，毒性很大。最近发现的一种炎症损伤机制“聚（adp -核糖）合成酶（PARS）途径”，现在已涉及胰岛细胞异体移植排斥反应的发病机制。PARS激活诱导AP-1依赖性促炎基因表达，消耗NAD，导致ATP耗竭和细胞能量衰竭。在这项提议中，我们提供了实验证据，证明药物抑制PARS活性和基因消融PARS基因具有有效的抗炎作用，并延长同种异体移植物的存活时间。Inotek正在开发一种高效、特异性、无毒、专有的PARS抑制剂，5-碘-6-氨基-1,2-苯并吡酮（INH2BP）。本研究的具体目的是在胰岛细胞移植实验模型中确定INH2BP在预防移植失败早期和晚期细胞损伤和功能障碍方面的益处。在该模型中，INH2BP可预防组织损伤，延长移植物存活和功能，这将是胰岛移植排斥反应的新型抗炎方案设计的突破，并将为其进一步的商业开发提供依据。拟议的商业应用：预防胰岛细胞排斥反应的新型有效疗法的国内市场估计为每年5亿美元。全球市场估计为20亿美元。目前的市场进入者具有相当大的毒性。INH2BP可能是首个高效且成功的候选疗法；SBIR第一期和第二期的资金将允许在3.5年内进入市场。

Inflammation and rejection are the principal obstacles to the use of pancreatic islet cell transplantation for the treatment of insulin-dependent diabetes mellitus. Current treatment regimens have limited efficacy and substantial toxicity. A recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) Pathway", has now been implicated in the pathogenesis of pancreatic islet cell allograft rejection. PARS activation induces AP-1 dependent pro-inflammatory gene expression and consumes NAD, resulting in ATP depletion and cellular energetics failure. In this proposal, we present experimental evidence that pharmacologic inhibition of PARS activity and genetic ablation of the PARS gene have potent anti-inflammatory effects and prolong allograft survival. Inotek is developing a highly potent, specific, non-toxic, and proprietary PARS inhibitor, 5-iodo-6-amino-1,2-benzopyrone (INH2BP). The specific aims of the present proposal are to determine the benefit of INH2BP in the prevention of cellular injury and dysfunction in the early and late phases of graft failure in an experimental model of pancreatic islet cell transplantation. The demonstration that INH2BP prevents tissue injury and prolongs graft survival and functions in this model would represent a breakthrough in the design of novel anti-inflammatory regimens for islet transplant rejection and would justify its further commercial development. PROPOSED COMMERCIAL APPLICATION: The domestic market for a novel, effective therapy to prevent pancreatic islet cell rejection is estimated at $500 million per annum. Global markets are estimated at $2 billion. Current market entrants have substantial toxicity. INH2BP may represent the first highly potent and successful candidate therapy; funding of SBIR Phase I and II will allow for market entry in 3.5 years.