Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk

Douglas Moeckel, Soon Soeg Jeong, Xiaofeng Sun, M. Johan Broekman, Annie Nguyen, Joan H.F. Drosopoulos, Aaron J. Marcus, Simon C. Robson, Ridong Chen, Dana Abendschein

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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.

Original languageEnglish
Article number248ra105
JournalScience translational medicine
Volume6
Issue number248
DOIs
StatePublished - Aug 6 2014

Fingerprint Dive into the research topics of 'Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk'. Together they form a unique fingerprint.

  • Cite this

    Moeckel, D., Jeong, S. S., Sun, X., Broekman, M. J., Nguyen, A., Drosopoulos, J. H. F., Marcus, A. J., Robson, S. C., Chen, R., & Abendschein, D. (2014). Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk. Science translational medicine, 6(248), [248ra105]. https://doi.org/10.1126/scitranslmed.3009246