Novel antioxidant catalyst for transplant rejection

描述(由申请人提供)：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疗效有限，且存在较大的毒性。移植肾损伤的一个关键的最终共同途径是由自由基一氧化氮和由一氧化氮和超氧阴离子反应形成的强氧化剂过氧亚硝酸盐介导的。伊诺克正在开发一种新型的过氧亚硝酸盐分解催化剂，这种催化剂在氧化剂介导的炎症性疾病的实验模型中具有显著的保护作用，包括自身免疫性关节炎、糖尿病和结肠炎。这些试剂从根本上优于传统的抗氧化剂：首先，它们是催化剂，而不是清除剂，因此不会消耗在氧化剂物种的分解中。其次，它们的反应速度超过1亿，比维生素C和维生素E等经典抗氧化剂快100多万倍。第三，它们对过氧亚硝酸盐和过氧化氢都有深刻的活性，因此提供了针对氧化和亚硝化压力的广谱保护。体内研究证实了它们的戏剧性效力，口服剂量在每公斤微克范围内的各种炎症模型的保护证明了这一点。在实验性疾病模型中，它们已被证明可以消除结肠炎，提高内毒素休克的存活率，并大大减少缺血再灌注期间的组织损伤。本建议的具体目的是确定我们的过氧亚硝酸铅分解催化剂INO-1080在预防同种异位心脏移植排斥反应的实验性啮齿动物模型中器官功能障碍和细胞损伤方面的益处。我们将建立INO-1080单独和亚治疗剂量环孢素A的协同作用。证明INO-1080预防组织损伤和延长移植物存活将是设计新的抗炎方案以延长移植物存活的突破性进展。第二阶段的资金将支持IND提交所需的药代动力学、毒理学和药效学研究，以及FDA批准的临床第一阶段试验。

DESCRIPTION (provided by the applicant): 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 key final common pathway of allograft injury is mediated by the free radical nitric oxide and the potent oxidant, peroxynitrite, which is formed from the reaction of nitric oxide and superoxide anion. Inotek is developing a novel class of peroxynitrite decomposition catalysts that are dramatically protective in experimental models of oxidant-mediated inflammatory diseases, including autoimmune arthritis, diabetes, and colitis. These agents are fundamentally superior to conventional anti-oxidants: First, they act as catalysts, rather than scavengers, and are therefore not consumed in the decomposition of oxidant species. Second, their reaction rate is in excess of 100 million, more than I million fold faster than classic anti-oxidants such as Vitamin C and E. Third, they have profound activity against both peroxynitrite and hydrogen peroxide, and thus provide broad-spectrum protection against oxidative and nitrosative stress. In vivo studies confirm their dramatic potency, as evidenced by protection in various models of inflammation at oral doses in the microgram per kg range. In experimental disease models, they have been shown to eliminate colitis, increase survival in endotoxic shock, and profundly reduce tissue damage during ischemia-reperfusion. The specific aim of the present proposal is to determine the benefit of our lead peroxynitrite decomposition catalyst, INO-1080, in the prevention of organ dysfunction and cellular injury in an experimental rodent model of heterotopic cardiac allograft rejection. We will establish the synergy of INO-1080, alone and with sub-therapeutic dosing of cyclosporine A. Demonstration that INO-1080 prevents tissue injury and prolongs allograft survival would represent a breakthrough in the design of novel anti-inflammatory regimens to prolong allograft survival. Phase II funding would support pharamcokinetic, toxicology, and pharmacodynamic studies required for IND submission and FDA-sanctioned clinical Phase I trials.