Development of Peptide Inhibitor of Complement to treat neonatal asphyxial brain damage

摘要 该项目的假设是，抑制经典补体途径 与补体C1肽抑制剂（PIC 1）的联合应用将在以下大鼠模型中具有神经保护作用： 新生儿缺氧缺血性脑病（HIE）。缺氧缺血性脑病是一种脑缺血再灌注损伤， 大脑在出生时发生，死亡率高达60%，幸存者中有25% 有严重残疾补体系统，最有效的炎症级联反应， 人，和炎症，吞噬细胞募集和直接细胞的关键介质 在动物模型中，已经显示在HIE的发病机制中起主要作用， 人类研究治疗性低温是新生儿HIE唯一可接受的治疗方法， 改善HIE的短期生存和神经发育，但没有显著改善 长期成果。到目前为止，没有一种测试的药理学佐剂用于治疗 低温已经证明了临床改善。引发剂分子C1 q缺乏 在动物模型中， 新生儿HIE我们目前的先导化合物PIC 1（PA-CPEG），是多年的产品， 合理的药物设计，产生与PEG缀合的15个氨基酸的肽。我们的化合物 与C1 q结合，在级联反应的第一步有效阻断补体激活。试点 在新生儿缺氧缺血性脑病的成熟Vannucci大鼠模型中的实验表明，PIC 1 显著减少脑梗塞体积，并减少神经元损伤。拟议的研究 将在Vannucci模型中完善PIC 1的剂量和频率，并进行全功率 评估PIC 1减少新生儿缺氧缺血性脑病脑损伤的功效的研究。的成功 拟议的研究将提供关键的概念验证，即PIC 1可以阻止补体- 介导的发病机制。这将提供必要的 通过药代动力学和药物动力学， 通过SBIR第2阶段进行毒理学研究。第三方市场分析显示， HIE中PIC 1的健康销量。第三方监管分析表明， 通过寻求孤儿药和突破性药物的指定来简化监管方法。

Abstract The hypothesis for the proposed project is that inhibition of the classical complement pathway with Peptide Inhibitor of complement C1 (PIC1) will be neuroprotective in a rat model of neonatal hypoxic-ischemic encephalopathy (HIE). HIE is an ischemia-reperfusion injury of the brain that occurs around the time of birth, with up to 60% mortality and 25% of survivors left with a significant disability. The complement system, the most potent inflammatory cascade in humans, and a critical mediator of inflammation , phagocytic cell recruitment and direct cell lysis, has been shown to play a major role in the pathogenesis of HIE in animal models and human studies. Therapeutic hypothermia, the only accepted treatment for neonatal HIE, slightly improves short-term survival and neurodevelopment in HIE, but does not significantly improve long-term outcomes. To date, none of the tested pharmacological adjuvants to therapeutic hypothermia have demonstrated clinical improvement. Deficiency of C1q, the initiator molecule of the classical complement pathway, has been shown to be neuroprotective in an animal model of neonatal HIE. Our current lead compound of PIC1 (PA-CPEG), is the product of years of rational drug design yielding a 15 amino acid peptide conjugated with PEG. Our compound binds to C1q, efficiently blocking complement activation at the first step in the cascade. Pilot experiments in the well-established Vannucci rat model of neonatal HIE have shown that PIC1 significantly reduces brain infarct volumes, and reduces neuronal injury. The proposed studies will refine dosing and frequency of PIC1 in the Vannucci model, and conduct fully powered studies to evaluate the efficacy of PIC1 in reducing brain injury in neonatal HIE. The success of the proposed studies will provide critical proof-of-concept that PIC1 can prevent complement- mediated pathogenesis in an animal model of human disease. This will provide the necessary evidence to propel the future pre-clinical development of PIC1 through pharmacokinetic and toxicology studies via SBIR Phase 2. Third-party market analysis shows the potential for healthy sales volumes for PIC1 in HIE. Third-party regulatory analysis suggests the potential for a stream-lined regulatory approach by seeking Orphan Drug and Breakthrough designations.