CTRIP: MMP1-PAR1-based Interventions in Arterial Thrombosis

描述（由申请人提供）：这项GO拨款申请的拟议研究旨在转化我们最近发现的一种新的治疗靶点，血小板上的MMP1-PAR1。利用各种动物模型和人类血液样本，我们确定了一种由血小板表面的基质金属蛋白酶-1 （MMP-1）驱动的凝血机制。我们发现MMP-1在血小板暴露于血管壁的胶原蛋白后以自分泌的方式激活蛋白酶激活受体-1 （PAR1）。阻断MMP1-PAR1通路的治疗可以阻止胶原存在下的血凝块形成，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性血栓性疾病和急性冠状动脉综合征患者提供新的途径。在这个应用中，我们建议使用我们的新Pepducin技术作为一种新的治疗方法来预防急性情况下胶原- mmp1 - par1动脉血栓形成。肽肽是一种脂化肽，靶向其同源受体的细胞质表面并中断内部G蛋白的信号传导。其中一种基于par1的肽蛋白PZ-128 （P1pal-7）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在啮齿类动物中被证明是安全且耐受性良好的，每天给药40-70天。在该CTRIP项目的第一阶段，将进行IND-enabling研究，以评估PZ-128在豚鼠和非人类灵长类动物中的有效性，以及在GLP条件下使用GMP材料的另外两种物种的安全性和毒理学。将设计临床试验来评估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个月的批准期结束时，主要的里程碑将是向FDA提交研究者发起的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为期五年的二期CTRIP临床研究。

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.