Complement inhibitors targeted to the ischemic brain for the treatment of stroke

重组组织型纤溶酶原激活剂（tPA）是目前唯一批准的用于治疗糖尿病的药物。 缺血性中风的治疗，一般必须在症状发作后4.5小时内给药。 由于这种时间限制，以及与这种药物有关的危险，估计只有大约5- 10%的中风患者接受tPA治疗。因此，迫切需要新的有效办法 来治疗中风现在清楚的是，补体系统在大肠杆菌的传播中起着重要作用。 脑缺血和再灌注（缺血性卒中）后的炎症和损伤，以及 本项目旨在开发和表征一种新型、有效和安全的位点靶向补体策略， 可以在中风后几小时应用的抑制，这将改善长期的认知和 功能恢复为了确定最有效的补体抑制方法，我们将准备和 表征阻断补体途径的不同部分的各种补体抑制剂， 通过一种新的方法靶向缺血性脑损伤部位。将使用 小鼠大脑中动脉闭塞和再灌注模型，我们将研究我们的影响， 脑损伤、修复和神经再生，以及急性和慢性认知和运动 功能成果。在鉴定了补体抑制构建体的最佳类型之后，我们将 完成一系列临床前测定，这将有助于未来的药物开发。这些研究将 包括PK和PD测定、剂量反应、治疗窗、给药时间表和对年轻人影响 和老年小鼠（因为中风的风险随着年龄的增长而增加）。最后，我们将研究我们的战略， 在tPA治疗的背景下进行补体抑制，以确定是否存在任何不良反应 与两种药理学试剂的联合给药相关。

Recombinant tissue-type plasminogen activator (tPA) is currently the only approved pharmacological agent for the treatment of ischemic stroke, and in general it must be administered within 4.5 hours of symptom onset. Because of this time constraint, as well as dangers associated with this drug, it is estimated that only about 5- 10% of stroke patients are treated with tPA. There is thus a significant need for new and effective approaches to treat stroke. It is now clear that the complement system plays an important role in the propagation of inflammation and injury following cerebral ischemia and reperfusion (ischemic stroke), and the overall goal of this project is to develop and characterize a novel, effective and safe strategy of site-targeted complement inhibition that can be applied several hours after stroke, and that will improve long-term cognitive and functional recovery. To identify the most effective complement inhibitory approach, we will prepare and characterize various complement inhibitors that block different parts of the complement pathway and that are targeted to the site of ischemic brain injury via a novel approach. The constructs will be investigated using a mouse model of middle cerebral artery occlusion and reperfusion, and we will investigate the effect of our constructs on cerebral injury, repair and neuroregeneration, and acute and chronic cognitive and motor function outcomes. Following identification of the optimum type of complement inhibitory construct, we will complete a series of pre-clinical determinations that will assist in future drug development. These studies will include PK and PD determinations, dose response, treatment window, dosing schedule, and effect in young and aged mice (since the risk of stroke increases with age). Finally, we will investigate our strategy of complement inhibition in the context of tPA therapy to determine whether there are any adverse effects associated with co-administration of the two pharmacological reagents.