CTRIP: MMP1-PAR1-based Interventions in Arterial Thrombosis

描述（由申请人提供）：该GO资助申请的拟议研究旨在转化我们最近发现的血小板上的新治疗靶点MMP 1-PAR 1。使用各种动物模型和来自人类的血液样本，我们确定了由血小板表面上的基质金属蛋白酶-1（MMP-1）驱动的凝血机制。我们发现，MMP-1激活蛋白酶激活受体-1（PAR 1）在自分泌的方式后，血小板暴露于胶原从血管壁。阻断MMP 1-PAR 1通路的治疗可以防止胶原蛋白存在时血栓形成，这表明靶向这种金属蛋白酶受体系统的药物可以为治疗动脉粥样硬化血栓形成疾病和急性冠状动脉综合征患者提供一种新的方法。在本申请中，我们提出使用我们的新型Pepducin技术作为一种新的治疗方法来预防急性环境中的胶原-MMP 1-PAR 1动脉血栓形成。肽蛋白是脂化肽，其靶向其同源受体的细胞质表面并中断向内部定位的G蛋白的信号传导。这些基于PAR 1的肽蛋白之一PZ-128（P1 pal-7）已经在动物中进行了广泛的测试，并被证明在抑制PAR 1依赖性血小板活化、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已被证明在啮齿动物中以高剂量每日给药40-70天时是安全的且耐受性良好。在该CTRIP项目的第一阶段，将进行IND使能研究，以评估PZ-128在豚鼠和非人灵长类动物中的疗效，以及在GLP条件下使用GMP材料在其他两个种属中的安全性和毒理学。将设计临床试验以评估PZ-128在正常志愿者和冠状动脉疾病患者中的安全性和有效性。这些研究将与美国多个学术、临床和CRO研究实验室合作进行。在24个月的授权期结束时，主要的里程碑将是向FDA提交由制药商发起的IND申请。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I期和II期临床研究，作为为期五年的第2阶段CTRIP奖。 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死亡的主要潜在原因，其中大多数死亡是由于冠心病和中风。考虑到动脉粥样硬化血栓形成疾病的高患病率和高MI和死亡率以及不良反应（出血和其他安全性问题）的发生率，对于新的治疗剂（如PZ-128所例示的）仍然存在高度未满足的需求，所述新的治疗剂可以靶向血小板的胶原蛋白和凝血酶依赖性活化而不过度影响止血。

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.