Multicenter preclinical trial of rho-kinase inhibitor fasudil in acute focal cerebral ischemia and reperfusion

Rho激酶抑制剂法舒地尔治疗急性局灶性脑缺血再灌注的多中心临床前试验

基本信息

批准号：
10246264
负责人：
Cenk Ayata
金额：
$ 53.08万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2019-09-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246264
关键词：
Actins Acute Adhesions Advocate Alteplase Anti-Inflammatory Agents Apoptosis Aspirin Blood - brain barrier anatomy Blood Cells Blood Vessels Blood Viscosity Brain Edema Cardiovascular system Carotid Atherosclerotic Disease Cerebral Infarction Cerebral Ischemia Cerebrovascular Circulation China Chronic Clinical Clinical Trials Coagulation Process Common Data Element Complement Core-Binding Factor Coronary Arteriosclerosis Cyclic AMP-Dependent Protein Kinases Cytoskeleton Diabetes Mellitus Dose Edema Endothelium Experimental Models Failure Female Filament Formulation Functional disorder Heart failure Hemorrhage Hypertension Imaging Device Inbred SHR Rats Infarction Inflammation Intervention Ischemia Ischemic Stroke Japan Leukocytes Magnetic Resonance Imaging Manuscripts Middle Cerebral Artery Occlusion Modeling Mus Neurocognitive Neuroglia Neurologic Neurons Non-Insulin-Dependent Diabetes Mellitus Outcome Outcome Assessment Patients Pharmaceutical Preparations Pharmacology Physiological Platelet aggregation Preclinical Testing Process Protein Kinase Publishing Pulmonary Hypertension Rattus Recording of previous events Reperfusion Therapy Research Personnel Rho-associated kinase Safety Sample Size Scientist Sensorimotor functions Series Serious Adverse Event Stroke Subarachnoid Hemorrhage Subgroup Swelling Testing Therapeutic Tissues Vascular Smooth Muscle Vasodilation acute care acute stroke aged atorvastatin blood-brain barrier disruption cerebrovascular clinically relevant comorbidity db/db mouse design efficacy evaluation efficacy testing efficacy trial environmental enrichment for laboratory animals excitotoxicity experience experimental study fasudil functional outcomes healthy volunteer hypercholesterolemia improved improved outcome indexing inhibitor/antagonist ischemic injury kinase inhibitor male molecular marker mortality natural hypothermia novel novel therapeutics off-patent optical imaging pre-clinical assessment preclinical trial protein kinase inhibitor research clinical testing response rho safety testing sex standard of care stroke model stroke patient stroke therapy support network systematic review thrombolysis tool treatment effect

项目摘要

In this preclinical trial, we propose to target rho-associated protein kinase (ROCK) using fasudil in models of acute focal cerebral ischemia followed by reperfusion. ROCK is a major regulator of actin cytoskeleton controlling numerous functions in vascular smooth muscle, endothelium, neurons, glia, leukocytes and blood cells. Many of these are relevant for the pathophysiology of stroke, making ROCK a unique pleiotropic target with multiple converging and synergistic mechanisms, including cerebrovasodilation and reduced blood viscosity improving collateral flow in hyperacute stroke, and anti-inflammatory and anti-edema effects in acute to subacute stages. We and others have targeted ROCK in models of ischemic stroke in exploratory studies, vast majority of which showed improved tissue and functional outcomes, in multiple species and stroke models, and using various inhibitors and therapeutic paradigms. In a systematic review and stratified metaanalysis of 25 experimental studies, ROCK inhibition reduced infarct volume by 37% and improved neurological scores by 41%. Fasudil is the most commonly used ROCK inhibitor in experimental stroke and is off-patent to be procured in any formulation for both preclinical and clinical trials without delay. Fasudil has been the clinical standard of care for two decades in acute SAH in China and Japan, with a clean safety record. There have been numerous clinical trials of systemic fasudil in both US and abroad in healthy volunteers, and in patients with chronic cerebral infarcts, coronary artery disease, heart failure, and pulmonary hypertension among others. Indeed, in a small trial in acute stroke fasudil was efficacious. Nevertheless, none of these trials revealed any serious adverse events either with acute single doses or chronic daily dosing. We propose to confirm this promising profile in a preclinical trial using transient middle cerebral artery occlusion. Aim 1 will establish the optimal dose (Exp 1), confirm efficacy on long-term outcome (Exp 2), test whether fasudil extends the therapeutic window for recanalization (Exp 3), examine the efficacy of intraarterial delivery (Exp 4), and confirm efficacy using clinically-relevant MRI indices (Exp 5). Aim 2 will then test efficacy and safety in a clot model with or without tPA (Exp 6), and safety in comorbid hypertension and diabetes as well as combination treatments (Exp 7) and in permanent ischemia (Exp 8). The proposal comes from an experienced group of investigators with proven expertise, capable of adjusting to the needs of the network. Collectively, we have published ~100 manuscripts using various stroke models and neurocognitive and tissue readouts suitable for both acute (<72h) and chronic (up to 2 months) assessments in mice and rats. Besides the proposed experimental models, our expertise covers hemorrhagic transformation, combination treatment with tPA and ischemic brain edema. Altogether, we passionately support the concept of an unbiased multicenter preclinical testing platform such as SPAN for experimental stroke therapeutics. We are fully committed to support this network.

在这项临床前试验中，我们建议在急性局灶性脑缺血模型中使用Fasudil靶向与Rho相关的蛋白激酶（岩石），然后再灌注。岩石是肌动蛋白细胞骨架的主要调节剂，该骨骼控制血管平滑肌，内皮，神经元，神经胶质，白细胞和血细胞中的许多功能。其中许多与中风的病理生理学有关，使岩石成为具有多种融合和协同机制的独特的多效性靶标，包括脑舒张和降低血液粘度，可改善超急性折磨的附带抗肌张力，以及抗炎和抗抑郁症的抗炎性和抗肿瘤效应。在探索性研究中，我们和其他人对缺血性中风模型的岩石有针对性的岩石，其中绝大多数显示了在多种物种和中风模型中的组织和功能结果的改善，并使用了各种抑制剂和治疗性范式。在对25项实验研究的系统综述和分层的荟萃分析中，岩石抑制作用使梗塞量减少了37％，并提高了神经系统评分41％。 Fasudil是实验性中风中最常用的岩石抑制剂，在临床前和临床试验的任何配方中都不得不毫不延迟地采购。在中国和日本的急性SAH急性SAH，Fasudil一直是临床护理标准，并具有清晰的安全记录。在健康志愿者中，美国和国外的全身性法做以及慢性脑梗塞，冠状动脉疾病，心力衰竭和肺动脉高压等患者进行了许多全身性法苏迪的临床试验。确实，在一次急性中风的小型试验中，法苏迪尔是有效的。尽管如此，这些试验都没有发现任何严重的不良事件，既不是急性单剂量或慢性每日给药。我们建议在临床前试验中使用瞬时脑中动脉闭塞确认这一有希望的概况。 AIM 1将建立最佳剂量（EXP 1），确认对长期结局的功效（EXP 2），测试Fasudil是否扩展了重新启动的治疗窗口（EXP 3），检查肉毒内递送的功效（EXP 4），并确认使用临床上相关的MRI指数（EXP 5）确认疗效。然后，AIM 2将在具有或没有TPA的凝块模型中测试功效和安全性（EXP 6），合并症高血压和糖尿病的安全性以及组合处理（EXP 7）和永久性缺血（EXP 8）。该提案来自经验丰富的研究人员，具有良好的专业知识，能够适应网络的需求。总的来说，我们使用各种中风模型以及适合于小鼠和大鼠的急性（<72H）和慢性（最多2个月）评估的神经认知和组织读数发表了〜100本手稿。除了提出的实验模型外，我们的专业知识还涵盖了出血转化，与TPA和缺血性脑水肿的联合治疗。总的来说，我们热情地支持公正的多中心临床前测试平台，例如用于实验性中风疗法的SPAN。我们完全致力于支持该网络。