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

急性缺血性中风(AIS)是成人致残的主要原因。再灌注疗法是FDA批准的唯一治疗AIS的方法，但由于治疗时间窗口较短，因此受到限制。我们认为，开发新的卒中治疗方法的一个非常有希望的方法是在卒中发病后早期开始使用神经保护剂，以在再灌注治疗之前或在再灌注治疗时减少梗塞的进展。我们团队发现IL-6受体阻滞剂tocilizumab(一种FDA批准的治疗类风湿性关节炎的药物)在减少脑梗塞体积和改善中风啮齿动物模型中的神经结局方面具有深远的神经保护作用，无论是雄性还是雌性，以及老年动物。这项建议的主要目的是确定tocilizumab是否确实可以减缓梗塞的进展，并延长静脉注射t-PA在高度临床相关的血栓栓塞术模型和缝合模型中用于再灌注治疗的治疗窗口，该模型可以作为机械血栓切除术(MT)的替代(特定目标2)。为了设计一项临床试验来测试血栓切除术的疗效，我们将在模拟中风发生率和严重程度的临床危险因素的各种临床相关模型中确定tocilizumab是否可以延长t-PA和MT的治疗窗口。这些模型包括高龄、高血压、糖尿病，并将检查两性(特定目标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，作为联盟努力的一部分，我们将开始与其他招募到SPAN的中心进行初步沟通，以建立评估其他候选药物的最佳方法(特定目标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的多年专业知识来评估其他候选治疗方案。

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.