CTRIP: MMP1-PAR1-based Interventions in Arterial Thrombosis

CTRIP：基于 MMP1-PAR1 的动脉血栓形成干预措施

• 批准号: 7855775
• 负责人: ATHAN KULIOPULOS
• 金额: $ 109.84万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7855775
• 关键词: Acute; Adverse effects; Affect; American; American Heart Association; Animal Model; Animals; Applications Grants; Arterial Fatty Streak; Atherosclerosis; Award; Blood Clot; Blood Platelets; Blood Vessels; Blood coagulation; Blood specimen; Canis familiaris; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cavia; Cessation of life; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Collagen; Conduct Clinical Trials; Coronary Arteriosclerosis; Coronary heart disease; Data; Death Rate; Disease; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Event; Funding; GTP-Binding Proteins; Grant; Health Benefit; Heart; Hemorrhage; Hemostatic function; High Prevalence; Human; In Vitro; Incidence; Individual; Infusion procedures; Interstitial Collagenase; Intervention; Laboratories; Laboratory Research; Lead; Life; Long-Term Effects; MAPK14 gene; Maryland; Massachusetts; Metalloproteases; Michigan; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Myocardial Infarction; Oregon; PAR-1 Receptor; Papio; Pathway interactions; Patients; Peptides; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase I/II Trial; Phase II Clinical Trials; Platelet Activation; Plavix; Production; Public Health; Rattus; Research Contracts; Research Design; Research Personnel; Rodent; Rupture; Safety; Signal Transduction; South Carolina; Staging; Stroke; Surface; System; Technology; Testing; Therapeutic; Thrombin; Thrombosis; Thrombus; Toxic effect; Toxicology; Translating; United States; United States National Institutes of Health; Wisconsin; acute coronary syndrome; autocrine; base; bivalirudin; design; in vivo; inhibitor/antagonist; neurobehavioral; new therapeutic target; nonhuman primate; novel; novel therapeutics; percutaneous coronary intervention; prevent; programs; public health relevance; receptor; respiratory; safety study; small molecule; tirofiban; volunteer

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.

描述（由申请人提供）：本次 GO 拨款申请的拟议研究旨在转化我们最近发现的血小板新治疗靶点 MMP1-PAR1。使用各种动物模型和人类血液样本，我们确定了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，血小板暴露于血管壁胶原蛋白后，MMP-1 以自分泌方式激活蛋白酶激活受体 1 (PAR1)。阻断 MMP1-PAR1 通路的治疗可防止胶原蛋白存在下形成血栓，这表明针对这种金属蛋白酶受体系统的药物可以为治疗动脉粥样硬化血栓性疾病和急性冠状动脉综合征患者提供新方法。在此应用中，我们建议使用我们的新型 Pepducin 技术作为一种新的治疗方法，以预防急性情况下胶原蛋白-MMP1-PAR1 动脉血栓形成。 Pepducins 是脂化肽，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 pepducins PZ-128 (P1pal-7) 已在动物身上进行了广泛测试，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。已证明 PZ-128 在啮齿类动物中每日高剂量给药 40-70 天是安全且耐受性良好的。在该 CTRIP 计划的第一阶段，将进行 IND 授权研究，以评估 PZ-128 在豚鼠和非人类灵长类动物中的功效，以及在 GLP 条件下使用 GMP 材料在其他两个物种中的安全性和毒理学。临床试验将旨在评估 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。 24 个月授权期结束时的主要里程碑将是研究者发起的 IND 向 FDA 提交。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，作为为期五年的第二阶段 CTRIP 奖励。 公共卫生相关性：根据美国心脏协会提供的最新数据，心血管疾病仍然是美国主要的死亡原因，其中大多数死亡是由于冠心病和中风。鉴于动脉粥样硬化血栓性疾病的高患病率、高心梗和死亡率以及不良反应（出血和其他安全问题）的发生率，对以 PZ-128 为代表的新疗法的需求仍然很高，未得到满足，该疗法可以靶向胶原蛋白和凝血酶依赖性血小板活化，而又不会过度影响止血。