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

急性缺血性中风（AIS）是导致成人残疾的主要原因。再灌注治疗是FDA批准的唯一治疗AIS的方法，但由于治疗时间窗狭窄，治疗效果有限。我们认为，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早期开始使用神经保护剂，以减少再灌注治疗前或时的梗死进展。我们的研究小组发现，IL-6受体阻滞剂tocilizumab （FDA批准的用于类风湿性关节炎的药物）在减少雄性、雌性和老年动物中风啮齿动物模型的梗死面积和改善神经系统预后方面具有深刻的神经保护作用。该提案的主要目的是确定tocilizumab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作为机械取栓（MT）替代的缝合模型中延长静脉t-PA再灌注治疗的治疗窗口（Specific Aim 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tocilizumab是否可以在各种临床相关模型中延长t-PA和MT的治疗窗口，这些模型模拟了中风发病率和严重程度的临床危险因素。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）。假设我们将被要求加入卒中临床前评估网络（SPAN）来测试tocilizumab，作为联盟工作的一部分，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（Specific Aim 3）。作为SPAN活动的一部分，我们当然愿意参与并利用我们多年来在转化性卒中研究方面的专业知识来评估其他候选治疗方法。

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.