Therapeutic to Reduce Acute Inflammation Following Cardiac Ischemia

描述（由申请人提供）：急性心肌梗死（AMI）每年影响超过100万美国人，目前除了直接经皮冠状动脉介入治疗外，没有预防性治疗。DecImmune的长期目标是开发治疗方法，以减少冠状动脉阻塞清除后严重的致命性再灌注损伤。这一目标是基于我们鉴定出一种新的途径，该途径通过缺血组织的再灌注和阻断炎症的肽模拟物（N2）和单克隆抗体的开发而被激活。目前的建议是重新提交的申请，遵循我们完成了早期第一阶段赠款的里程碑。修订后的应用程序解决了审查人员的担忧，并包括大量的新结果，例如更详细和完整的方案以及增加猪的数量以提高统计功效。我们早期的研究表明，我们在啮齿动物中发现的新途径在人类中是保守的。因此，为了将潜在的治疗方法转移到临床试验中，我们建议在猪模型中扩展我们的观察。鉴于与人类血管系统的高度生理相似性，猪代表了良好的动物模型。II期申请目标的成功实现将导致在I期临床试验中测试治疗剂。 公共卫生相关性：美国每年有超过120万人心脏病发作。尽管溶栓治疗和血管成形术取得了进展，但仍有25%的男性和38%的女性在心脏病发作后一年内死亡。高发病率和死亡率的一个重要因素是由于缺血和再灌注部位的急性炎症对心脏组织造成的损伤。该项目的目标是开发一种治疗化合物，该化合物将抑制心肌梗死后患者缺血部位发生的急性炎症，最大限度地减少微血管损伤并保护梗死区的存活心肌细胞。本申请中描述的研究将把我们对抑制剂的测试扩展到猪急性心肌梗死模型。

DESCRIPTION (provided by applicant): Acute myocardial infarction (AMI) affects over 1 million US individuals a year and at present there are no preventative therapeutics other than direct percutaneous coronary intervention. DecImmune's long-term goal is to develop therapeutics to reduce the severe lethal reperfusion injury that follows removal of coronary artery blockage. This goal is based on our identification of a novel pathway that is activated by reperfusion of ischemic tissues and development of a peptide mimetope (N2) and monoclonal antibodies that block inflammation. The current proposal is a resubmission of an application that follows from our completion of the milestones of an earlier Phase I grant. The revised application addresses the concerns of the reviewers and includes substantial new results such as a more detailed and complete protocol and an increased number of pigs to enhance statistical power. Our earlier studies demonstrated that the novel pathway we identified in rodents is conserved in humans. Therefore, in order to move the potential therapeutics to clinical trials, we propose to extend our observations in a pig model. Given the high degree of physiological similarities with the human vascular system, pigs represent a good animal model. Successful achievement of the goals of the Phase II application will lead to testing of the therapeutics in Phase I clinical trials. PUBLIC HEALTH RELEVANCE: There are over 1.2 million heart attacks annually in the US. In spite of advances made in thrombolytic therapy and angioplasty, up to 25% of men and 38% of women die within one year following a heart attack. A significant factor in the high morbidity and mortality is due to the damage that is caused to the cardiac tissues by acute inflammation at the site of ischemia and reperfusion. The goal of this project is to develop a therapeutic compound that will inhibit the acute inflammation that occurs at the site of ischemia in patients following a myocardial infarction, minimizing the amount of microvascular damage and protecting viable cardiac cells in the infarct zone. Studies described in the application will extend our testing of the inhibitors to a swine model of acute myocardial infarction.