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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.

急性缺血性卒中（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。我们认为，开发新的卒中治疗方法的一个非常有前途的方法是在卒中发作后早期启动神经保护剂，以减少再灌注治疗前或再灌注治疗时的梗死进展。我们的研究小组发现，IL-6受体阻断剂托珠单抗（一种FDA批准的用于类风湿性关节炎的药物）在减少雄性和雌性以及老年动物中风啮齿动物模型中的梗死体积和改善神经学结果方面具有深刻的神经保护作用。该提案的主要目的是确定托珠单抗是否确实可以减缓梗死进展，并在高度临床相关的血栓栓塞模型和可用作机械血栓切除术（MT）替代品的缝合模型中使用IV t-PA延长再灌注治疗的治疗窗（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各种临床相关模型中延长t-PA和MT的治疗窗，这些模型模拟了卒中发生率和严重程度的临床风险因素。这些模型包括高龄、高血压、糖尿病，并将对两性进行检查（具体目标3）。假设我们将被要求加入卒中临床前评估网络（SPAN），以测试托珠单抗，作为联盟工作的一部分，我们将开始与招募到SPAN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卒中研究方面的多年专业知识来评估其他候选治疗方案。