Therapeutic Protein C Activator for Myocardial Ischemia

治疗心肌缺血的蛋白 C 激活剂

• 批准号: 8456004
• 负责人: Erik Ian Tucker
• 金额: $ 26.09万
• 依托单位: ARONORA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-05 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456004
• 关键词: Acute; Acute myocardial infarction; Address; Adverse effects; Animal Model; Animals; Anticoagulation; Apoptosis; Applications Grants; Area; Autoantibodies; Award; Binding; Biological Assay; Bleeding time procedure; Blood Clot; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Blood specimen; Cardiac; Cause of Death; Cell Line; Cell surface; Cells; Cessation of life; Coagulation Process; Complex; Coronary Care Units; Coronary Stenosis; Coronary artery; Cyclic GMP; Cytoprotection; Defense Mechanisms; Development; Disease; Disease Progression; Dosage Forms; Dose; Drug Kinetics; Early treatment; Emergency Situation; Emergency treatment; Enzyme Activators; Enzymes; Evolution; Factor Va; Fibrin; Functional disorder; Generations; Grant; Hemorrhage; Hemostatic function; Hirudin; Hirudins; Hospitalization; Hospitals; Hour; Human; Immune response; Immunoglobulin G; Impairment; Infarction; Ischemia; Ischemic Stroke; Left; Measures; Medical; Modeling; Monitor; Mus; Muscle; Myocardial Infarction; Myocardial Ischemia; Myocardium; Outcome; Papio; Patients; Perfusion; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Pre-Clinical Model; Prevention; Primates; Protein C; Recombinants; Reperfusion Injury; Reperfusion Therapy; Research; Risk; Rupture; Safety; Signal Transduction; Site; Small Business Innovation Research Grant; Stenosis; Stroke prevention; Surface; Testing; Therapeutic; Thrombin; Thrombin Time Assay; Thrombomodulin; Thrombosis; Thrombus; Time; Toxicology; Treatment Cost; United States; United States National Institutes of Health; Vascular Graft; activated Protein C; analog; artery occlusion; attack victim; base; blood vessel occlusion; commercialization; drug candidate; high risk; human subject; immunogenicity; improved; in vivo; innovation; man; mortality; mouse model; muscle necrosis; neutralizing antibody; novel; pre-clinical; prevent; product development; programs; public health relevance; receptor; secondary outcome; success; therapeutic protein; treatment strategy

DESCRIPTION (provided by applicant): Rapidly progressing occlusion of the coronary artery and the subsequent acute myocardial ischemia is the most prevalent primary cause of acute myocardial infarction (AMI) and death in the United States. Early recanalization and antithrombotic therapy promotes reperfusion and improves outcomes when administered before completion of the infarct. However, most heart attack victims do not receive causal treatments to support reperfusion or inhibit progression before they reach the hospital, because current treatments, although effective, are difficult to deliver and carry a risk of severe or fatal hemorrhage. Less severe cases reach the hospital alive, sometimes within an hour from onset, and results from the causal outcomes in these patients are reasonably good; nevertheless, many victims are left without causal treatment in the most critical initial minutes to hours. Despite medical advances, more than a third of AMI victims die of their disease, with acute mortality that surpasses all other causes of death. Since time is of the essence in halting the rapid development of terminal muscle infarction and delayed treatment costs many lives, there is a major unmet medical need for a safe treatment. A safe emergency measure is needed that could be used in any patient, without limitation, as early as at the time of presentation, before the patient reaches the hospital. Our product candidate, a recombinant selective protein C activator (PCA) enzyme, ProCaseTM, is intended to address this unmet need. PCAs are recombinant thrombin analogs. ProCase is a first-in-class, unique drug candidate that currently stands without comparison or competition. Injected ProCase binds to cellular receptors and acts locally by multiple mechanisms, including induction of a potent defense mechanism by generation of endogenous activated protein C (APC) on intravascular surfaces and competitive inhibition of the platelet receptor GPIb. Endogenous protein C activation is a natural and essential defense mechanism that normally acts through cytoprotective (antiapoptotic) signaling, and through inactivation of plasma factors Va and VIIIa. Exploiting this natural mechanism, ProCase generates endogenous APC that protects cells from apoptosis, and inhibits blood vessel occlusions without systemic anticoagulation and hemostasis impairment. We have previously demonstrated the safety and efficacy of several PCAs in preclinical models of thrombosis and stroke prevention in primates and mice, respectively. We now hypothesize that, when administered during acute myocardial ischemia, ProCase may have significant cardioprotective potential and can interrupt progressive coronary artery occlusions that cause rapidly developing irreversible heart muscle necrosis. Our initial research objective is to evaluate the therapeutic potential of ProCase in an animal model of reversible myocardial ischemia. The Specific Aims for this Fast-track Phase I/II SBIR grant application are to: 1) Evaluate the therapeutic potential of ProCase treatment in a mouse model of AMI; 2) Determine the antithrombotic potential of ProCase treatment during experimental vaso-occlusive thrombosis in primates; 3) Define the pharmacokinetics of ProCase; and 4) Evaluate the immunogenicity of ProCase in primates. If successful, this research will support the hypothesis that selective intravascular protein C activation is a promising early treatment strategy to interrupt the progression of acute myocardial ischemia before its evolution into acute cardiac dysfunction or terminal AMI. Reaching our milestones will prompt the initiation of formal product development towards an IND for the emergency treatment of suspected and/or verified myocardial ischemia.

描述（由申请人提供）：冠状动脉的快速闭塞和随后的急性心肌缺血是美国急性心肌梗塞（AMI）和死亡的最普遍的主要原因。在梗塞完成之前进行早期再通和抗血栓治疗可促进再灌注并改善预后。然而，大多数心脏病发作患者在到达医院之前并没有接受支持再灌注或抑制进展的因果治疗，因为目前的治疗虽然有效，但难以实施，并且存在严重或致命出血的风险。不太严重的病例可以活着到达医院，有时在发病后一小时内就可以到达医院，而且这些患者的因果结果相当不错；然而，许多受害者在最关键的最初几分钟到几小时内没有得到因果治疗。尽管医学取得了进步，但仍有超过三分之一的 AMI 患者死于疾病，其急性死亡率超过了所有其他死因。由于时间对于阻止终末肌梗塞的快速发展至关重要，并且延迟治疗会导致许多人丧生，因此安全治疗的医疗需求尚未得到满足。需要一种安全的紧急措施，该措施可以不受限制地应用于任何患者，早在就诊时、患者到达医院之前即可使用。我们的候选产品是一种重组选择性蛋白 C 激活剂 (PCA) 酶 ProCaseTM，旨在解决这一未满足的需求。 PCA 是重组凝血酶类似物。 ProCase 是一种一流的、独特的候选药物，目前没有比较或竞争。注射的 ProCase 与细胞受体结合，并通过多种机制发挥局部作用，包括通过在血管内表面生成内源性活化蛋白 C (APC) 来诱导有效的防御机制，以及竞争性抑制血小板受体 GPIb。内源性蛋白 C 激活是一种天然且重要的防御机制，通常通过细胞保护（抗凋亡）信号传导以及血浆因子 Va 和 VIIIa 的失活发挥作用。利用这种自然机制，ProCase 产生内源性 APC，保护细胞免于凋亡，并抑制血管闭塞，而不会损害全身抗凝和止血功能。我们之前已经分别在灵长类动物和小鼠的血栓形成和中风预防的临床前模型中证明了几种 PCA 的安全性和有效性。我们现在假设，在急性心肌缺血期间施用时，ProCase 可能具有显着的心脏保护潜力，并且可以中断进行性冠状动脉闭塞，从而导致快速发展的不可逆心肌坏死。我们最初的研究目标是评估 ProCase 在可逆性心肌缺血动物模型中的治疗潜力。此快速通道 I/II 期 SBIR 拨款申请的具体目标是： 1) 评估 ProCase 治疗在 AMI 小鼠模型中的治疗潜力； 2) 确定 ProCase 治疗在灵长类动物实验性血管闭塞性血栓形成过程中的抗血栓潜力； 3) 定义ProCase的药代动力学； 4) 评估 ProCase 在灵长类动物中的免疫原性。如果成功，这项研究将支持这样的假设：选择性血管内蛋白 C 激活是一种有前途的早期治疗策略，可以在急性心肌缺血演变为急性心功能不全或终末期 AMI 之前中断其进展。达到我们的里程碑将促使启动正式的产品开发，以用于紧急治疗疑似和/或已证实的心肌缺血的 IND。