PARS INHIBITOR FOR ISLET CELL TRANSPLANT REJECTION

用于胰岛细胞移植排斥的 PARS 抑制剂

• 批准号: 2802531
• 负责人: JON G MABLEY
• 金额: $ 10万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-13 至 2000-04-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2802531
• 关键词: ADP ribosylation; adenine phosphoribosyltransferase; antiinflammatory agents; artificial immunosuppression; cell line; drug design /synthesis /production; enzyme inhibitors; laboratory rat; pancreatic islet transplantation; transplant rejection

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.

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。目前的治疗方案具有有限的疗效和显著的毒性。最近发现的炎症损伤机制，“聚（ADP-核糖）合成酶（PARS）途径”，现在已经涉及胰岛细胞移植排斥反应的发病机制。PARS活化诱导AP-1依赖性促炎基因表达并消耗NAD，导致ATP耗竭和细胞能量学失败。在这个建议中，我们提出的实验证据表明，药物抑制PARS活性和基因消融的PARS基因有强大的抗炎作用，延长同种异体移植物的存活。Inotek正在开发一种高效、特异、无毒和专有的PARS抑制剂5-碘-6-氨基-1，2-苯并吡喃酮（INH 2BP）。本提案的具体目的是确定INH 2BP在胰岛细胞移植实验模型中预防移植失败早期和晚期细胞损伤和功能障碍的益处。INH 2BP在该模型中预防组织损伤和胰岛移植物存活和功能的证明将代表在设计用于胰岛移植排斥的新型抗炎方案方面的突破，并将证明其进一步的商业开发是合理的。拟定商业应用：一种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。目前的市场进入者有很大的毒性。INH 2BP可能是第一个高效和成功的候选疗法; SBIR I期和II期的资金将允许在3.5年内进入市场。