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Stroke Preclinical Assessment Network (SPAN) – Tacilizumab for treatment of acute ischemic stroke

卒中临床前评估网络 (SPAN) – 他珠单抗治疗急性缺血性卒中

基本信息

批准号：
10214711
负责人：
Jaroslaw Aronowski
金额：
$ 50.69万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2019-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214711
关键词：
3-Dimensional Acute Adult Alteplase Animal Model Animals Area Arteries Atrophic Binding Blinded Blocking Antibodies Brain Brain Edema Caring Cell Death Cerebral Ischemia Cerebrum Clinical Clinical Trials Coagulation Process Cognitive Communication Data Diabetes Mellitus Diffusion Magnetic Resonance Imaging Dose Elderly Excision FDA approved Failure Female Filament Giant Cells Goals Guidelines Half-Life Hemorrhage Histologic Hour Human Hypertension Immunoglobulin G Infarction Infection Inflammation Infrastructure Interleukin 6 Receptor Interleukin-6 Ischemic Stroke Laboratories Link Measures Mechanics Mediating Methods Modeling Motor Mus Neurologic Deficit Neurological outcome Neuroprotective Agents Outcome Outcome Assessment Oxidative Stress Patients Perfusion Pharmaceutical Preparations Physiological Play Preclinical Testing Process Randomized Rattus Reperfusion Therapy Reproducibility Research Research Personnel Retrieval Rheumatoid Arthritis Risk Factors Rodent Rodent Model Role Safety Severities Stroke Surgical sutures Testing Therapeutic Therapeutic Agents Thrombectomy Thromboembolism Time Translations United States United States National Institutes of Health Withdrawal aged aging population base brain tissue clinical risk clinically relevant comorbidity cost cytokine design disability drug candidate efficacy testing functional outcomes histological image humanized antibody improved interest male mortality neuroprotection post stroke pre-clinical pre-clinical assessment preservation primary outcome receptor recruit secondary outcome sex stroke incidence stroke model stroke patient stroke therapy thrombolysis tocilizumab

项目摘要

Acute ischemic stroke (AIS) is the leading cause of adult disability. Reperfusion therapies are the only FDA approved treatments for AIS but are limited because of narrow therapeutic time windows. We believe a highly promising approach to develop new stroke treatments is to initiate a neuroprotective agent early after stroke onset to reduce infarct progression before, or at the time of, reperfusion therapy. Our group has found that the IL-6 receptor blocker tocilizumab, (an FDA approved medication used for rheumatoid arthritis) is profoundly neuroprotective in reducing infarct volume and improving neurological outcome in rodent models of stroke in males and females and in aged animals. The primary objective of this proposal is to determine if tocilizumab can indeed slow infarct progression and extend the therapeutic window for reperfusion therapy using IV t-PA in a highly clinically relevant thromboembolic model and in a suture model that could be applied as a surrogate of the mechanical thrombectomy (MT) (Specific Aim 2). In order to design a clinical trial to test the efficacy of thrombectomy, we will then determine if tocilizumab can extend the therapeutic window of t-PA and MT in various clinically relevant models that simulate clinical risk factors for stroke incidence and severity. These models include advanced age, hypertension, diabetes, and will examine both sexes (Specific Aim 3). Assuming we will be asked to join the Stroke Preclinical Assessment Network (SPAN) to test tocilizumab as part of the consortium effort, we will begin initial communications with the other centers recruited to SPAN to establish optimal approaches to evaluate other candidate drugs (Specific Aim 3). We will certainly be willing to participate and use our many years of expertise in translational stroke research to evaluate other treatment candidates as part of the SPAN activities.

急性缺血性中风（AIS）是成人残疾的主要原因。再灌注疗法是 FDA 唯一批准的 AIS 治疗方法，但由于治疗时间窗狭窄而受到限制。我们相信，开发新的中风治疗方法的一个非常有前途的方法是在中风发作后尽早启动神经保护剂，以在再灌注治疗之前或再灌注治疗时减少梗塞进展。我们的研究小组发现，IL-6 受体阻滞剂托珠单抗（FDA 批准的用于治疗类风湿性关节炎的药物）在雄性和雌性以及老年动物的中风啮齿动物模型中具有显着的神经保护作用，可减少梗塞体积并改善神经系统结果。该提案的主要目的是确定托珠单抗是否确实可以减缓梗塞进展并延长在临床高度相关的血栓栓塞模型和缝合模型中使用 IV t-PA 进行再灌注治疗的治疗窗，该模型可用作机械血栓切除术 (MT) 的替代品（具体目标 2）。为了设计一项临床试验来测试血栓切除术的疗效，我们将确定托珠单抗是否可以在模拟中风发病率和严重程度的临床危险因素的各种临床相关模型中延长 t-PA 和 MT 的治疗窗。这些模型包括高龄、高血压、糖尿病，并将检查两性（具体目标 3）。假设作为联盟工作的一部分，我们将被要求加入中风临床前评估网络 (SPAN) 来测试托珠单抗，我们将开始与 SPAN 招募的其他中心进行初步沟通，以建立评估其他候选药物的最佳方法（具体目标 3）。作为 SPAN 活动的一部分，我们当然愿意参与并利用我们在转化性中风研究方面多年的专业知识来评估其他候选治疗方法。