Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk.
Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk.
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DOI：
10.1126/scitranslmed.3009246
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发表时间：
2014-08-06
影响因子：
17.1
通讯作者：
Abendschein D
中科院分区：
文献类型：
--
作者：
Moeckel D;Jeong SS;Sun X;Broekman MJ;Nguyen A;Drosopoulos JH;Marcus AJ;Robson SC;Chen R;Abendschein D
在接受再灌注治疗以恢复通过阻塞动脉的血流的急性心肌梗死患者中，同时抑制血小板P2 Y12受体与当前标准治疗既不能完全预防复发性血栓形成，也不能对再灌注损伤提供令人满意的保护。此外，这些抗血小板药物会增加出血的风险。为了设计不同的策略，我们设计并优化了人三磷酸核苷二磷酸水解酶-3（CD 39 L3）的腺苷三磷酸双磷酸酶活性，以增强对细胞外二磷酸腺苷（P2 Y12受体的主要配体）的清除。所得到的重组蛋白，APT 102，表现出大于四倍高的腺苷二磷酸酶活性和50倍长的血浆半衰期比天然腺苷三磷酸双磷酸酶。在清醒的狗中，在冠状动脉纤溶之前静脉注射重组人组织型纤溶酶原激活剂，用APT 102治疗完全防止血栓性再闭塞，并使梗死面积显著减少81%，而不增加出血时间。相反，氯吡格雷不能预防冠状动脉再闭塞和增加出血时间。在短暂冠状动脉闭塞引起的心肌再灌注损伤的小鼠模型中，APT 102也使梗死面积减少了51%，而氯吡格雷无效。这些临床前数据表明，APT 102应测试其安全有效地最大化动脉血栓形成患者心肌再灌注治疗获益的能力。
In patients with acute myocardial infarction undergoing reperfusion therapy to restore blood flow through blocked arteries, simultaneous inhibition of platelet P2Y12 receptors with the current standard of care neither completely prevents recurrent thrombosis nor provides satisfactory protection against reperfusion injury. Additionally, these antiplatelet drugs increase the risk of bleeding. To devise a different strategy, we engineered and optimized the apyrase activity of human nucleoside triphosphate diphosphohydrolase-3 (CD39L3) to enhance scavenging of extracellular adenosine diphosphate, a predominant ligand of P2Y12 receptors. The resulting recombinant protein, APT102, exhibited greater than four times higher adenosine diphosphatase activity and a 50 times longer plasma half-life than did native apyrase. Treatment with APT102 before coronary fibrinolysis with intravenous recombinant human tissue-type plasminogen activator in conscious dogs completely prevented thrombotic reocclusion and significantly decreased infarction size by 81% without increasing bleeding time. In contrast, clopidogrel did not prevent coronary reocclusion and increased bleeding time. In a murine model of myocardial reperfusion injury caused by transient coronary artery occlusion, APT102 also decreased infarct size by 51%, whereas clopidogrel was not effective. These preclinical data suggest that APT102 should be tested for its ability to safely and effectively maximize the benefits of myocardial reperfusion therapy in patients with arterial thrombosis.
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