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)是目前唯一被批准的治疗 治疗缺血性中风，一般来说，必须在症状出现后4.5小时内使用。 由于时间的限制，以及与这种药物相关的危险，估计只有大约5- 10%的中风患者接受tPA治疗。因此，迫切需要新的有效方法。 治疗中风。现在很清楚，补体系统在补体的传播中起着重要的作用 脑缺血和再灌流(缺血性中风)后的炎症和损伤，以及 该项目旨在开发和表征一种新的、有效的和安全的定点补体策略 可以在中风后几个小时应用的抑制，这将改善长期认知和 功能恢复。为了确定最有效的补体抑制方法，我们将准备和 表征各种补体抑制剂，它们阻断补体途径的不同部分， 通过一种新的方法定位于缺血性脑损伤的部位。这些构造将使用 建立小鼠大脑中动脉闭塞再灌流模型，观察其对小鼠大脑中动脉闭塞再灌注损伤的影响。 关于脑损伤、修复和神经再生以及急性和慢性认知和运动的结构 功能结果。在确定补体抑制结构的最佳类型之后，我们将 完成一系列有助于未来药物开发的临床前检测。这些研究将 包括PK和PD测定、剂量反应、治疗窗口、给药计划和对年轻人的影响 以及衰老的小鼠(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治疗的背景下抑制补体以确定是否有任何不良反应 与两种药理试剂的联合给药有关。

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.