Evaluation of combined anakinra and thrombolysis treatment for ischaemic stroke' to 'Targeting interleukin-1 as a therapy for neurological diseases

中风是世界范围内死亡率和发病率的主要原因，治疗选择有限。唯一获得批准的治疗中风的药物是重组组织型纤溶酶原激活剂（rtPA），血管内血栓切除术最近被证明是一种改善预后的替代方法。虽然这些再灌注策略在符合条件的患者中有效，但这只占卒中总人群的一小部分（约20%），并且不适用于出血性卒中。因此，需要新的、更广泛可用的治疗方法，理想情况下可以用于所有中风亚型。我们和其他人已经表明，白细胞介素-1 （IL-1）是神经元损伤的关键介质，并且用IL-1受体拮抗剂（阿那金）阻断IL-1的作用在不同的中风模型中具有保护作用，阿那金在缺血性和出血性中风中的早期临床试验是有希望的。与目前正在开发的任何其他药物相比，Anakinra拥有一些最有力的现有证据来支持其在中风中的应用，并且于2018年10月开始了一项用于蛛网膜下腔出血的III期研究。我们最近对阿那金在缺血性卒中中的2期研究显示，与安慰剂相比，阿那金通过减少炎症改善了临床结果。然而，分析也揭示了另一种导致更差结果的途径，我们不能排除rtPA与anakinra合用可能是导致这一结果的原因。因此，迫切需要更详细地探索rtPA和阿那金之间的潜在相互作用，然后再进一步开发阿那金作为缺血性卒中的新治疗方法。因此，本项目的总体目的是通过临床相关的血栓栓塞性脑卒中啮齿动物模型，了解rtPA与阿那白拉治疗缺血性脑卒中之间的关系。主要目标是：(1)确定临床研究中阿那白素和rtPA之间的任何假设相互作用是否可以在血栓栓塞性中风的啮齿动物模型中复制(2)确定阿那白素和rtPA治疗的最佳时机，以及再灌注是否重要(3)进一步探索阿那白素在rtPA给药之外的其他神经系统疾病中的治疗潜力。正在评估功能和组织病理学结果。在进行体内脑卒中研究的同时，我们还将在体外确定anakinra和rtPA之间是否存在任何直接相互作用。为了实现这些目标，我们将确定在未来的anakinra临床试验中联合治疗所需的特定给药方案。

Stroke is a leading cause of mortality and morbidity worldwide with limited treatment options. The only licensed drug treatment for stroke is recombinant tissue plasminogen activator (rtPA), with endovascular thrombectomy recently being shown as an alternative approach that improves outcome. While these reperfusion strategies can be effective in eligible patients this represents a small percentage (~20%) of the overall stroke population, and they are not applicable in haemorrhagic stroke. New, more widely available treatments, ideally that could be used in all stroke sub-types, are therefore required.We and others have shown that interleukin-1 (IL-1) is a key mediator of neuronal injury and that blocking IL-1 actions with the IL-1 receptor antagonist (anakinra) is protective in different stroke models and that early stage clinical trials of anakinra in both ischaemic and haemorrhagic stroke are promising. Anakinra has some of the strongest available evidence to support its use in stroke compared to any other drug in current development and a phase III study in subarachnoid haemorrhage commenced in October 2018.Our recent Phase 2 study of anakinra in ischaemic stroke revealed that, compared to placebo, anakinra improved clinical outcome by reducing inflammation. However, analysis also revealed an alternative pathway leading to worse outcome, and we cannot rule out that co-administration of rtPA with anakinra might contribute to this. There is therefore an urgent need to explore any potential interaction between rtPA and anakinra in more detail before anakinra can be further developed as a new treatment in ischaemic stroke. Therefore, the overall aim of this project is to understand the relationship between rtPA and anakinra treatment in ischaemic stroke, using clinically relevant rodent models of thromboembolic stroke.The primary objectives are to:(1) Establish if any postulated interaction between anakinra and rtPA in clinical studies can be replicated in rodent models of thromboembolic stroke(2) Establish the optimal timings of anakinra and rtPA treatment and if reperfusion is important(3) Further explore the therapeutic potential of anakinra in other neurological diseases beyond rtPA administrationWe will use well-described thromboembolic stroke models in mice with imaging, functional and histopathological outcomes being assessed. In parallel to the in vivo stroke studies we will also determine in vitro whether there is any direct interactions between anakinra and rtPA.In addressing the objectives we will have identified the need for a specific dosing regimen that is required for combined treatment in future clinical trials of anakinra.