Combination Treatment of tPA and Apyrase for Stroke

描述(申请人提供)：人apyrase代表了一种非常有希望的治疗急性缺血性中风的方法，它是导致死亡和残疾的主要原因，对大多数患者来说几乎没有有效的治疗方法。利用蛋白质信息学的方法，我们成功地设计出一种人apyrase，它比野生型apyrase具有显著更高的酶活性和血小板抑制作用。重要的是，优化的apyrase在预防脑出血的同时，对实验性中风提供了脑保护。在第二阶段赠款的支持下，我们将确定apyrase疗法是否比阿司匹林和GPIIb/IIIa受体拮抗剂与r-tPA联合用于中风闭塞的溶栓治疗更有效，出血风险更低。 公共卫生相关性：我们将利用临床相关的大鼠栓塞性卒中模型来验证人类apyrase是否改善了与缺血性卒中溶栓治疗相关的疗效和减少脑出血。

DESCRIPTION (provided by applicant): Human apyrase represents a highly promising therapy for acute ischemic stroke which is a leading cause of death and disability with almost no effective therapy for most patients. Using a protein informatics approach, we have successfully engineered a human apyrase which exhibits significantly higher enzymatic activity and platelet inhibition than the wild-type apyrases. Importantly, the optimized apyrase conferred cerebroprotection against experimental stroke while preventing intracerebral hemorrhage. With the Phase II grant support, we will determine whether apyrase therapy is more effective while having lower bleeding risk than aspirin and a GPIIb/IIIa receptor antagonist, in combination with r-tPA for thrombolysis of stroke occlusion. PUBLIC HEALTH RELEVANCE: We will utilize clinically relevant embolic stroke models in rats to validate whether human apyrase improves efficacy and reduce cerebral hemorrhage associated with thrombolytic treatment of ischemic stroke.