Apyrase to Treat Ischemia/Reperfusion Injury during Lung Transplantation

描述(由申请人提供)：人apyrase是一种非常有希望的治疗方法，可以减少由于不可避免的获取、保存和恢复血流的过程而导致的10%-20%的肺移植受者的缺血/再灌注损伤。这种临床情况，最近被称为原发移植物功能障碍，仍然是肺移植后的一个重要问题，并且仍然是肺移植受者早期发病率和死亡率的最大原因。Apyrase强烈抑制血小板活化和炎症，并有适度的出血风险。利用蛋白质信息学的方法，我们成功地设计出一种凝血靶向人apyrase APT202，它比野生型apyrase表现出显著更高的酶活性和血小板抑制作用。在第一阶段SBIR赠款的支持下，我们将优化APT202的给药方案，在已建立的动物移植模型中保持低出血风险的同时，提供显著的益处。最终目标是将APT202推向临床，从改善氧合、缩短机械通气时间和住院时间等方面改善患者的预后。人apyrase代表了一种非常有希望的治疗方法，以减少肺移植相关的缺血/再灌注损伤。我们将优化一种凝血靶向apyrase的剂量方案，该方案将在已建立的动物移植模型中提供显著的益处，同时保持低出血风险。

DESCRIPTION (provided by applicant): Human apyrase represents a highly promising therapy to reduce ischemia/reperfusion injury which occurs in10-20% of lung transplant recipients as the consequence of unavoidable processes of procurement, preservation and restoring blood flow. This clinical condition, recently termed primary graft dysfunction, remains an important problem after lung transplantation, and still represents the single biggest cause of early morbidity and mortality for lung recipients. Apyrase strongly inhibits platelet activation and inflammation with modest bleeding risk. Using a protein informatics approach, we have successfully engineered a clot-targeting human apyrase, APT202, which exhibits significantly higher enzymatic activity and platelet inhibition than the wild-type apyrase. With the Phase I SBIR grant support, we will optimize the dose regimen of APT202 that will provide significant benefits while maintaining low bleeding risk in established animal transplantation models. The ultimate goal is to advance APT202 into clinic to improve patient outcome in terms of oxygenation improvement, reduction for duration of mechanical ventilation and hospital stay. Human apyrase represents a highly promising therapy to reduce ischemia/reperfusion injury associated with lung transplantation. We will optimize the dose regimen of a clot- targeting apyrase that will provide significant benefits while maintaining low bleeding risk in established animal transplantation models.