Therapeutic to Reduce Acute Inflammation Following Cardiac Ischemia

减少心脏缺血后急性炎症的治疗

• 批准号: 7109773
• 负责人: ELISABETH M ALICOT-CARROLL
• 金额: $ 12.92万
• 依托单位: DECIMMUNE THERAPEUTICS, INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7109773
• 关键词: affinity chromatography; antiantibody; antigen antibody reaction; biological models; cardiovascular disorder therapy; enzyme linked immunosorbent assay; gene expression; genetically modified animals; immunoglobulin M; immunotherapy; inflammation; laboratory mouse; myocardial ischemia /hypoxia; myosins; pathologic process; protein binding; protein structure; reperfusion; surface plasmon resonance

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.

描述（由申请人提供）：再灌注损伤（RI）是一种病因不明的严重危及生命的炎症过程，发生在血流返回缺血组织时，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的起始中起关键作用。该公司已在小鼠模型中分离出第一种致病性天然抗体，鉴定了这种抗体的特异性缺血抗原靶标，并制备了肽模拟表位。当在缺血之前或之后不久施用这些肽时，阻断小鼠肠和后肢肌肉的再灌注损伤，并防止小鼠心脏中缺血和再灌注后的心肌梗塞。 这项资助的目的是确定在小鼠中鉴定的天然抗体和缺血性抗原的特异性在人类中是否保守。研究设计将利用在小鼠研究中开发的试剂和动物模型，并将其应用于人体组织和血液样本的评价。 成功的结果将导致一种治疗化合物的开发，用于预防心脏缺血后的急性炎症。该公司预计，其第一个产品将是肽或阻断剂（例如，抗体、Aptimer或其它结合剂），其将在心脏直视手术之前施用于患者。美国每年进行超过690，000例心脏直视手术。这些患者中约12%在手术后6个月内死亡或心脏病发作，并且RI是主要原因。此外，该化合物在治疗心肌梗死或中风后的患者方面具有显着的潜力。