Preventing Neurovascular Matrix Degradation and Hemorrhage in Acute Ischemic Stroke

预防急性缺血性中风的神经血管基质降解和出血

• 批准号: 10683359
• 负责人: Sun Yong Jeong
• 金额: $ 128.3万
• 依托单位: TRANSLATIONAL SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683359
• 关键词: Acute; Address; Adverse event; Affinity; Alteplase; Biochemistry; Bioreactors; Blood Vessels; Blood coagulation; Blood flow; Brain; Brain Edema; Brain Infarction; Brain Ischemia; Brain hemorrhage; Cause of Death; Cessation of life; Chinese Hamster Ovary Cell; Clinical Trials; Complement; Data; Development; Disabled Persons; Disease; Dose; Drug Kinetics; Early treatment; Edema; Evaluation; Experimental Models; Failure; Gelatinase B; Goals; Growth; Health Care Costs; Hemorrhage; Human; Infarction; Intracranial Hemorrhages; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Lead; Left; Matrix Metalloproteinase Inhibitor; Medical; Metalloproteases; Minority; Modeling; Monoclonal Antibodies; Mus; Neurologic; Neurological outcome; Outcome; Patients; Peptide Hydrolases; Persons; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Pre-Clinical Model; Preparation; Production; Productivity; Protein Engineering; Recombinants; Recommendation; Recovery; Reperfusion Therapy; Research; Research Personnel; Risk; Role; Safety; Severities; Small Business Innovation Research Grant; Stroke; Swelling; Testing; Therapeutic; Therapeutic Studies; Therapeutic antibodies; Thrombus; Time; Tissues; Toxicology; Translational Research; Treatment Efficacy; antibody inhibitor; artery occlusion; behavior prediction; blood-brain barrier crossing; cGMP production; cell bank; clinical development; comparative; cross reactivity; disability; effective therapy; endovascular thrombectomy; extracellular; high volume manufacturing; human tissue; improved; inhibitor; manufacturability; manufacturing process; mortality; neurobehavioral; neurovascular; nonhuman primate; novel therapeutics; pharmacokinetics and pharmacodynamics; pharmacologic; phase I trial; pre-Investigational New Drug meeting; pre-clinical; preclinical safety; preclinical study; prevent; response; small molecule; stroke therapy; targeted treatment

Each year ~12 million people each year suffer from an ischemic stroke. Millions are left disabled and ~3 million die. Treatment with recombinant tissue plasminogen activator (r-tPA) treatment significantly reduces patient disability. However, r-tPA therapy does not reduce mortality and it causes some form of brain hemorrhage in up to 30% of patients. In selected r-tPA-treated patients with large vessel occlusions, endovascular thrombectomy significantly improves reperfusion and outcome, but it also carries a comparable risk of intracranial hemorrhage. Unfortunately, there is no proven effective therapy for brain hemorrhage, which causes disability and is the major cause of early mortality in r-tPA-treated patients. A safer treatment for ischemic stroke, used in combination with these therapies, which reduces hemorrhage, as well as brain infarction and brain edema, could save lives, reduce patient disability and lower health care costs. To address this need, Translational Sciences, Inc. seeks to develop an ultra-specific therapeutic to selectively target matrix metalloproteinase-9 (MMP-9) in the vascular compartment. Levels of MMP-9 rise acutely in the vascular compartment of the brain in response to ischemia and r-tPA therapy. MMP-9 is a protease that degrades the neurovascular matrix and contributes to ischemic brain injury and hemorrhage. Small molecule, broad spectrum MMP inhibitors block MMP-9 activity, but these agents may cross the blood brain barrier and inhibit both harmful and protective metalloproteinases, which appears to contribute to their failure in clinical trials. To address these limitations, Translational Sciences, Inc. developed a high-affinity, ultra-specific MMP-9 inhibitor that selectively targets MMP-9 in the vascular compartment. When this lead monoclonal antibody inhibitor was added to r-tPA therapy, even after prolonged ischemia, it markedly reduced brain hemorrhage, infarction, swelling, neurobehavioral disability and death in experimental ischemic stroke. In Phase I of this project, we successfully converted this monoclonal antibody into a recombinant, first-in-class, therapeutic MMP-9 inhibitor. In this Phase II proposal, we will follow FDA guidance and specific pre-IND meeting recommendations, to further develop this novel therapeutic for the treatment of ischemic stroke, by completing key milestones such as master cell bank creation, bioreactor production, release testing and pivotal safety-toxicology studies in preparation for an IND.

每年约有1200万人患有缺血性中风。数百万人残疾， 死的用重组组织型纤溶酶原激活剂（r-tPA）治疗显著降低了患者的 残疾。然而，r-tPA治疗并不能降低死亡率，而且在高血压患者中会引起某种形式的脑出血。 30%的患者。在选定的接受r-tPA治疗的大血管闭塞患者中， 显著改善了再灌注和预后，但也有相当的颅内出血风险。 不幸的是，目前还没有有效的治疗脑出血，这导致残疾，是主要的 r-tPA治疗患者早期死亡的原因。缺血性卒中的一种更安全的治疗方法，与 这些疗法可以减少出血、脑梗塞和脑水肿，可以挽救生命， 减少患者残疾和降低医疗保健成本。 为了满足这一需求，Translational Sciences，Inc.寻求开发一种超特异性治疗方法， 靶向基质金属蛋白酶-9（MMP-9）。MMP-9的水平急剧上升， 脑血管区室对缺血和r-tPA治疗的反应。MMP-9是一种蛋白酶， 神经血管基质，并有助于缺血性脑损伤和出血。小分子，宽 一系列MMP抑制剂阻断MMP-9活性，但这些药物可穿过血脑屏障并抑制MMP-9活性。 有害的和保护性的金属蛋白酶，这似乎有助于他们在临床试验中失败。到 解决这些局限性，Translational Sciences，Inc.开发了一种高亲和力、超特异性的MMP-9抑制剂， 选择性靶向血管区室中的MMP-9。当这种单克隆抗体抑制剂被 加入r-tPA治疗，即使在长时间缺血后，它也显著减少脑出血，梗塞， 肿胀、神经行为障碍和实验性缺血性卒中死亡。在本项目的第一阶段，我们 成功地将这种单克隆抗体转化为重组的、一流的、治疗性MMP-9抑制剂。 在本II期提案中，我们将遵循FDA指南和特定的IND前会议建议，以进一步 开发这种治疗缺血性中风的新型疗法，通过完成关键里程碑，如掌握 细胞库创建、生物反应器生产、放行检测和关键安全性毒理学研究， 一个IND。