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，没有其他预防性治疗方法。DecImmune的长期目标是开发治疗方法，以减少冠状动脉阻塞去除后严重的致命再灌注损伤。这一目标是基于我们对缺血组织再灌注激活的新途径的鉴定，以及肽模位（N2）和单克隆抗体阻断炎症的发展。目前的提案是在我们完成早期I期拨款里程碑之后重新提交申请。修订后的申请解决了审稿人关注的问题，并包括实质性的新结果，例如更详细和完整的方案，增加了猪的数量，以提高统计能力。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在生理上的高度相似性，猪是一种很好的动物模型。成功实现II期申请的目标将导致在I期临床试验中测试治疗方法。

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.