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

卒中是全球范围内死亡和发病的主要原因，治疗选择有限。唯一获得许可的卒中药物治疗是重组组织纤溶酶原激活剂（rtPA），最近显示血管内血栓切除术是改善结局的替代方法。虽然这些再灌注策略在合格患者中可能有效，但这仅占总卒中人群的一小部分（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，理想的是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，用IL-1受体拮抗剂（阿那白滞素）阻断IL-1的作用在不同的中风模型中具有保护作用，并且阿那白滞素在缺血性和出血性中风中的早期临床试验是有希望的。与目前开发的任何其他药物相比，阿那白滞素有一些最强有力的证据支持其在中风中的使用，并且蛛网膜下腔出血的III期研究于2018年10月开始。我们最近的阿那白滞素在缺血性中风中的II期研究显示，与安慰剂相比，阿那白滞素通过减少炎症改善了临床结局。然而，分析也揭示了导致更差结果的替代途径，我们不能排除rtPA与阿那白滞素联合给药可能对此有贡献。因此，在阿那白滞素被进一步开发为缺血性卒中的新治疗方法之前，迫切需要更详细地探索rtPA和阿那白滞素之间的任何潜在相互作用。因此，本项目的总体目标是使用临床相关的血栓栓塞性卒中啮齿动物模型，了解rtPA和阿那白滞素治疗在缺血性卒中中的关系。主要目标是：（1）确定临床研究中阿那白滞素和rtPA之间的任何假定相互作用是否可以在血栓栓塞性卒中的啮齿动物模型中复制（2）确定阿那白滞素和rtPA治疗的最佳时机以及再灌注是否重要（3）进一步探索阿那白滞素在rtPA给药以外的其他神经系统疾病中的治疗潜力我们将充分利用-描述了小鼠血栓栓塞性中风模型，并评估了成像、功能和组织病理学结果。在体内中风研究的同时，我们还将在体外确定阿那白滞素和rtPA之间是否存在任何直接的相互作用。在解决这些目标时，我们将确定在未来的阿那白滞素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.