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）：该GO赠款申请的拟议研究旨在翻译我们最近发现的新治疗靶标MMP1-PAR1在血小板上。使用来自人类的各种动物模型和血液样本，我们确定了一种血液凝结机制，该机制是由基质金属蛋白酶-1（MMP-1）在血小板表面驱动的。我们发现，在血小板从血管壁暴露于胶原蛋白后，MMP-1以自分泌方式激活蛋白酶激活的受体1（PAR1）。阻止MMP1-PAR1途径的治疗方法阻止了在存在胶原蛋白的情况下形成血凝块，这表明针对这种金属蛋白酶受体受体系统的药物可以为治疗患有动脉粥样硬化性疾病和急性冠状动脉综合症的患者提供一种新的方法。在此应用中，我们建议将新型的遍布蛋白技术用作一种新的治疗方法，以防止在急性环境中胶原蛋白MMP1-PAR1动脉血栓形成。胃蛋白是脂肪肽，靶向其同源受体的细胞质表面，并在内部置换G蛋白上中断信号传导。这些基于PAR1的胃蛋白之一PZ-128（P1PAL-7）已在动物中进行了广泛的测试，并证明在抑制PAR1依赖性血小板激活，胶原蛋白驱动的动脉血栓形成和动脉粥样硬化方面非常有效。当每天以高剂量服用40-70天时，PZ-128在啮齿动物中已显示出安全且耐受性良好。在该CTRIP计划的第一阶段，将进行辅助研究，以评估PZ-128在豚鼠和非人类灵长类动物中的功效，以及在GMP条件下具有GMP材料的其他两个物种的安全和毒理学。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功效。这些研究将与美国的多个学术，临床和CRO研究实验室合作进行。 24个月赠款期末的主要里程碑将是调查员对FDA的提交。如果成功，我们将在正常志愿者和急性冠状动脉综合症患者中进行I阶段和II期临床研究作为五年阶段2 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的主要根本死亡原因，其中大多数死亡是由于冠状动脉心脏病和中风造成的。鉴于动脉粥样硬化性疾病的高流行，高MI和死亡率以及不良反应的发生率（出血和其他安全问题），PZ-128的例子仍然存在很高的未满足需要的新治疗剂，可以针对胶原蛋白和依赖性依赖性的血小板激活而无需影响血小板的血小板。