Arise

出现

基本信息

批准号：
8484458
负责人：
Cenk Ayata
金额：
$ 90.5万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-20 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8484458
关键词：
Acute Adverse event Alteplase Aneurysmal Subarachnoid Hemorrhages Animal Model Anticoagulants Applications Grants Atherosclerosis Blood Vessels Blood flow Boston Brain Cardiovascular system Cause of Death Cerebrovascular Circulation Clinical Clinical Trials Coronary Arteriosclerosis Data Deterioration Diabetic mouse Dose Drug Kinetics Drug usage Economic Burden Evolution Hematology Heparin Hour Human Hypotension Intervention Intravenous Ischemic Stroke Japan Laboratories Maximum Tolerated Dose Measures Middle Cerebral Artery Occlusion Modeling Neurologic Patients Pattern Pharmaceutical Preparations Phase Pre-Clinical Model Protein Isoforms Protein Kinase Protein Kinase Inhibitors Quality of life ROCK1 gene Recommendation Reperfusion Therapy Research Design Risk Risk Factors Safety Salicylic Acids Spinal cord injury Stroke Subarachnoid Hemorrhage Surface Symptoms Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect Translational Research Translations Vascular Diseases Vasospasm Warfarin Work acute stroke atorvastatin brain tissue cell type design disability fasudil healthy volunteer improved liver function nervous system disorder neuroprotection novel novel therapeutic intervention preclinical study programs protein kinase inhibitor research clinical testing research study response rho safety testing standard of care therapeutic target thrombolysis translational study

项目摘要

The narrow therapeutic window of safety for thrombolysis limits its use in the majority of acute stroke patients. A broader range of reperfusion strategies with enhanced safety and efficacy profiles is needed. Inhibition of Rhoassociated protein kinase (ROCK) is one such therapeutic intervention. ROCK inhibitors improve cerebral blood flow (CBF) in ischemic brain, and have demonstrated efficacy in a variety of experimental stroke models. In this grant application, we propose to take the first translational step toward comprehensive clinical testing of ROCK as a therapeutic target in ischemic stroke. We identified a novel compound (SLx-2119; Surface Logix, Boston, MA) that is 100-fold more selective towards ROCK2 than ROCK1 and other protein kinases, and appears to have a more favorable safety profile. This compound is currently undergoing safety testing in healthy volunteers. We propose a 4-year translational study designed to confirm the efficacy of selective ROCK2 inhibition using SLx- 2119 in pre-clinical models (Years 1-2) and perform the first dose escalation toxicity study in 30 human stroke patients (Years 3-4). Aim 1: Test the safety and efficacy of SLx-2119 in experimental stroke. Building on preliminary data showing efficacy in a standard middle cerebral artery occlusion model, we propose to perform preclinical studies that are critical for translation of SLx-2119 from bench to human stroke. Aim 2: Test the safety of R0CK2 inhibition using SLx-2119 in acute ischemic stroke patients. We plan to conduct a Phase IB dose-finding study in ischemic stroke patients treated within 12 hours of symptom onset at escalating doses of SLx-2119. The primary aim is to evaluate the safety of SLx-2119, by identifying the maximum tolerated dose (MTD). In addition, we will assess the pharmacokinetics of SLx-2119, measure ROCK activity, and obtain additional human stroke safety data.

溶栓安全的狭窄治疗窗限制了其在大多数急性中风患者中的使用。需要更广泛的再灌注策略，并提高安全性和有效性。 Rho相关抑制蛋白激酶（ROCK）就是这样的一种治疗干预措施。 ROCK抑制剂改善脑血脑流（CBF）在缺血性脑中的作用，并已在各种实验性中风模型中证明了功效。在这个拨款申请中，我们建议迈出 ROCK 全面临床测试的第一步转化步骤作为缺血性中风的治疗靶点。我们鉴定了一种新型化合物（SLx-2119；Surface Logix，波士顿， MA）对 ROCK2 的选择性比 ROCK1 和其他蛋白激酶高 100 倍，并且似乎具有更有利的安全状况。该化合物目前正在健康志愿者中进行安全性测试。我们提出一项为期 4 年的转化研究，旨在确认使用 SLx- 选择性 ROCK2 抑制的功效 2119 在临床前模型（第 1-2 年）中进行，并在 30 例人类中风中进行首次剂量递增毒性研究患者（3-4 年级）。目标 1：测试 SLx-2119 在实验性卒中中的安全性和有效性。建立在初步数据显示在标准大脑中动脉闭塞模型中的功效，我们建议进行临床前研究对于 SLx-2119 从实验室转化为人类中风至关重要。目标 2：测试使用 SLx-2119 在急性缺血性中风患者中抑制 R0CK2 的安全性。我们计划进行 IB 阶段对缺血性中风患者进行的剂量探索研究，患者在症状出现后 12 小时内接受递增剂量的治疗 SLx-2119。主要目的是通过确定最大耐受剂量来评估 SLx-2119 的安全性（MTD）。此外，我们将评估SLx-2119的药代动力学，测量ROCK活性，并获得额外的人类中风安全数据。