http://stm.sciencemag.org/content/6/248/248ra105.abstract
- Douglas Moeckel1,
- Soon Soeg Jeong2,
- Xiaofeng Sun3,
- M. Johan Broekman4,5,
- Annie Nguyen1,
- Joan H. F. Drosopoulos4,5,
- Aaron J. Marcus4,5,
- Simon C. Robson3,
- Ridong Chen2,* and
- Dana Abendschein1,*
+ Author Affiliations
- ↵*Corresponding author. E-mail: rchen@apt-therapeutics.com (R.C.); dabendsc@DOM.wustl.edu (D.A.)
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.
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