Document Detail


Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk.
MedLine Citation:
PMID:  25100739     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
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.
Authors:
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
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Science translational medicine     Volume:  6     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2014 Aug 
Date Detail:
Created Date:  2014-08-07     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  248ra105     Citation Subset:  IM    
Copyright Information:
Copyright © 2014, American Association for the Advancement of Science.
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