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

基本信息

批准号：
10546521
负责人：
Sun Yong Jeong
金额：
$ 116.12万
依托单位：
TRANSLATIONAL SCIENCES, INC.
依托单位国家：
美国
项目类别：
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/10546521
关键词：
Acute Address Adverse event Affinity Alteplase Arteries Behavior Biochemistry Bioreactors Blood - brain barrier anatomy Blood Vessels Blood coagulation Blood flow Brain Brain Edema Brain Infarction Brain hemorrhage Cause of Death Cessation of life Chinese Hamster Ovary Cell Clinical Data 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 Matrix Metalloproteinases 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 antibodies Thrombus Time Tissues Toxicology Translational Research antibody inhibitor cGMP production cell bank clinical development comparative cross reactivity disability effective therapy endovascular thrombectomy extracellular human tissue improved inhibitor manufacturability manufacturing process meetings mortality neurobehavioral neurovascular nonhuman primate novel therapeutics pharmacokinetics and pharmacodynamics phase I trial pre-clinical preclinical safety preclinical study prevent response small molecule stroke therapy targeted treatment

项目摘要

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。数百万人致残，约 300 万人死。使用重组组织纤溶酶原激活剂 (r-tPA) 治疗可显着减少患者的病情残疾。然而，r-tPA 疗法并不能降低死亡率，反而会导致某种形式的脑出血。至 30% 的患者。在选定的接受 r-tPA 治疗的大血管闭塞患者中，进行血管内血栓切除术显着改善再灌注和预后，但也具有相当的颅内出血风险。不幸的是，对于脑出血还没有经过证实的有效治疗方法，脑出血会导致残疾，并且是主要的疾病。 r-tPA 治疗患者早期死亡的原因。缺血性中风的更安全治疗方法，与以下药物联合使用这些疗法可以减少出血、脑梗死和脑水肿，可以挽救生命，减少患者残疾并降低医疗保健费用。为了满足这一需求，Translational Sciences, Inc. 寻求开发一种超特异性疗法，以选择性地血管室中的靶基质金属蛋白酶-9 (MMP-9)。 MMP-9 水平急剧上升大脑血管室对缺血和 r-tPA 治疗的反应。 MMP-9 是一种蛋白酶，可降解神经血管基质并导致缺血性脑损伤和出血。小分子，宽广谱 MMP 抑制剂可阻断 MMP-9 活性，但这些药物可能会穿过血脑屏障并抑制有害和保护性金属蛋白酶，这似乎是其在临床试验中失败的原因。到为了解决这些限制，Translational Sciences, Inc. 开发了一种高亲和力、超特异性 MMP-9 抑制剂选择性地靶向血管室中的 MMP-9。当这种先导单克隆抗体抑制剂被与r-tPA治疗相结合，即使在长时间缺血后，也能显着减少脑出血、梗死、实验性缺血性中风中的肿胀、神经行为障碍和死亡。在这个项目的第一阶段，我们成功地将这种单克隆抗体转化为重组的一流治疗性 MMP-9 抑制剂。在此第二阶段提案中，我们将遵循 FDA 指导和具体的 IND 前会议建议，以进一步通过完成关键里程碑，例如大师，开发这种治疗缺血性中风的新型疗法细胞库创建、生物反应器生产、释放测试和关键安全毒理学研究，为 IND。