CTRIP: MMP1-PAR1-based Interventions in Arterial Thrombosis

描述(由申请人提供)：这项GO赠款申请的拟议研究旨在翻译我们最近发现的一种新的治疗靶点，血小板上的MMP1-PAR1。利用不同的动物模型和人类血液样本，我们确定了一种由血小板表面基质金属蛋白酶-1(MMP1)驱动的凝血机制。我们发现，当血小板暴露于血管壁胶原后，基质金属蛋白酶-1以自分泌的方式激活蛋白水解酶激活受体-1(PAR1)。阻断MMP1-PAR1途径的治疗可以防止在胶原存在的情况下形成血栓，这表明针对这种金属蛋白酶-受体系统的药物可能为治疗动脉粥样硬化性血栓性疾病和急性冠状动脉综合征患者提供一种新的方法。在这项应用中，我们建议使用我们的新型Pepducin技术作为一种新的治疗方法，以防止急性环境中的胶原-MMP1-PAR1动脉血栓形成。Pepducins是以其同源受体的细胞质表面为靶标的脂化肽，并中断信号转导位于内部的G蛋白。PZ-128(P1PAL-7)是其中一种基于PAR1的肽蛋白，已经在动物身上进行了广泛的测试，并被证明在抑制PAR1依赖的血小板激活、胶原驱动的动脉血栓形成和动脉粥样硬化方面非常有效。PZ-128已被证明是安全的，在啮齿类动物中耐受性良好，每天高剂量服用40-70天。在携程计划的第一阶段，将进行启用IND的研究，以评估PZ-128在豚鼠和非人类灵长类动物中的疗效，以及在GLP条件下使用GMP材料的另外两个物种的安全性和毒理学。临床试验将评估PZ-128在正常志愿者和冠心病患者中的安全性和有效性。这些研究将与美国各地的多个学术、临床和CRO研究实验室合作进行。在24个月的授权期结束时，主要的里程碑将是调查员发起的IND提交给FDA。如果成功，我们将在正常志愿者和急性冠状动脉综合征患者中进行为期五年的携程第二阶段奖，进行I期和II期临床研究。 公共卫生相关性：在美国心脏协会提供的最新数据中，心血管疾病仍然是美国主要的潜在死亡原因，其中大多数死亡是由于冠心病和中风。鉴于动脉粥样硬化性血栓疾病的高患病率、高心肌梗塞和高死亡率以及不良反应(出血和其他安全问题)的发生率，对新疗法的需求仍然很高，例如PZ-128，这种疗法可以针对胶原和凝血酶依赖的血小板激活，而不会过度影响止血。

DESCRIPTION (provided by applicant): The proposed studies of this GO grant application are designed to translate our recent discovery of a new therapeutic target, MMP1-PAR1 on platelets. Using various animal models and blood samples from humans, we identified a blood clotting mechanism that is driven by matrix metalloprotease-1 (MMP-1) on the platelet surface. We found that MMP-1 activates protease-activated receptor-1 (PAR1) in an autocrine manner after platelets are exposed to collagen from the blood vessel wall. Treatments that block the MMP1-PAR1 pathway prevented blood clots from forming in the presence of collagen, suggesting that drugs targeting this metalloprotease-receptor system could offer a new way to treat patients with atherothrombotic disease and acute coronary syndromes. In this application we propose to use our novel Pepducin technology as a new treatment to prevent collagen-MMP1-PAR1 arterial thrombosis in the acute setting. Pepducins are lipidated peptides which target the cytoplasmic surface of their cognate receptor and interrupt signaling to internally-located G proteins. One of these PAR1-based pepducins, PZ-128 (P1pal-7), has been extensively tested in animals and proven to be highly effective in inhibiting PAR1-dependent platelet activation, collagen-driven arterial thrombosis, and atherosclerosis. PZ-128 has been shown to be safe and well tolerated in rodents when administered daily at high doses for 40-70 days. In the first stage of this CTRIP program, IND-enabling studies will be conducted to assess efficacy of PZ-128 in guinea pigs and non-human primates, and safety and toxicology in two other species with GMP material under GLP conditions. Clinical trials will be designed to evaluate the safety and efficacy of PZ-128 in normal volunteers and in patients with coronary artery disease. These studies will be conducted in collaboration with multiple academic, clinical, and CRO research laboratories across the United States. The major milestone at the end of the 24 month grant period will be an investigator-initiated IND submission to the FDA. If successful, we will then conduct phase I and II clinical studies as a five-year Stage 2 CTRIP award in normal volunteers and patients with acute coronary syndromes. PUBLIC HEALTH RELEVANCE: In the most recent data supplied by the American Heart Association, cardiovascular disease remained the major underlying cause of death in the United States with the majority of these deaths being due to coronary heart disease and stroke. Given the high prevalence of atherothrombotic disease and high MI and death rates, and incidence of adverse effects (bleeding and other safety issues), there remains a high unmet need for new therapeutics as exemplified by PZ-128, that can target both collagen and thrombin-dependent activation of platelets without unduly affecting hemostasis.