Therapeutic to Reduce Acute Inflammation Following Cardiac Ischemia

描述(申请人提供)：再灌注损伤(RL)是一种原因不明的严重危及生命的炎症过程，当血流返回到缺血组织时，例如心脏病发作或心脏手术后的心肌。血流恢复到先前缺血的组织会导致心脏炎症和组织损伤。 Declmmune的研究现已证明，天然抗体在RL的启动过程中起着关键作用。该公司已经在小鼠模型中分离出第一个致病天然抗体，鉴定了这种抗体的特异性缺血抗原靶标，并制备了多肽模拟表位。这些多肽在缺血前或缺血后不久给药，可阻断小鼠肠道和后肢肌肉的再灌注损伤，并防止小鼠心脏缺血和再灌流后的心肌梗死。 这项资助的目的是确定在小鼠中识别的天然抗体和缺血抗原的特异性是否在人类中保留。研究设计将利用在小鼠研究中开发的试剂和动物模型，并将它们应用于人体组织和血液样本的评估。 成功的结果将导致开发一种治疗化合物，用于预防心脏缺血后的急性炎症。该公司预计，它的第一个产品将是一种多肽或封闭剂(例如抗体、适体或其他粘合剂)，将在心脏直视手术前用于患者。在美国，每年进行的心脏直视手术超过69万例。这些患者中约有12%在手术后6个月内死亡或心脏病发作，RL是主要原因。此外，该化合物可能在治疗心肌梗死或中风后的患者方面具有显著的潜力。

DESCRIPTION (provided by applicant): Reperfusion injury (Rl) is a serious life-threatening inflammatory process of unknown etiology that occurs when blood flow is returned to an ischemic tissue, for example heart muscle following a heart attack or cardiac surgery. The restoration of blood flow to previously ischemic tissue results in cardiac inflammation and tissue damage. Studies at Declmmune have now proven the pivotal role natural antibodies play in the initiation of Rl. The company has isolated the first pathogenic natural antibody in a mouse model, identified the specific ischemic antigen target of this antibody, and prepared peptide mimetopes. These peptides, when administered prior to or shortly after ischemia, block reperfusion injury to intestine and hind limb muscle in mice and prevent myocardial infarction following ischemia and reperfusion in the mouse heart. The aim of this grant is to determine if the specificity of the natural antibody and ischemic antigen identified in mice is conserved in humans. The research design will utilize the reagents and animal models that have been developed in the mouse studies and apply them to the evaluation of human tissue and blood samples. A successful outcome will lead to the development of a therapeutic compound to be used to prevent acute inflammation following cardiac ischemia. The company anticipates that its first product will be either a peptide or a blocking agent (e.g., antibody, aptimer, or other binder) that will be administered to patients prior to open heart surgery. More than 690,000 open heart procedures are performed in the US annually. Approximately 12% of these patients die or have a heart attack within 6 months of surgery and Rl is a major cause. In addition the compound could have significant potential in treating patients following myocardial infarction or stroke.