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Thrombus formation is initiated by platelets and leads to cardiovascular, cerebrovascular, and peripheral vascular disease, the leading causes of morbidity and mortality in the Western world. A number of antiplatelet drugs have improved clinical outcomes for thrombosis patients. However, their expanded use, especially in surgery, is limited by hemorrhage. Here, we describe an antiplatelet agent that can have its activity controlled by a matched antidote. We demonstrate that an RNA aptamer targeting von Willebrand factor (VWF) can potently inhibit VWF-mediated platelet adhesion and aggregation. By targeting this important adhesion step, we show that the aptamer molecule can inhibit platelet aggregation in PFA-100 and ristocetin-induced platelet aggregation assays. Furthermore, we show that a rationally designed antidote molecule can reverse the effects of the aptamer molecule, restoring platelet function quickly and effectively over a clinically relevant period. This aptamer-antidote pair represents a reversible antiplatelet agent inhibiting a platelet specific pathway. Furthermore, it is an important step towards creating safer drugs in clinics through the utilization of an antidote molecule.

The evolution of anticoagulant therapy for the prevention and treatment of thrombotic disorders has progressed at a relatively modest pace considering the scope of the problem and our current understanding of platelet biology, coagulation proteases, and vascular science as they apply to protective haemostasis and pathologic thrombosis. Recent observations, dedicated to cellular-based models of coagulation, provide fundamental constructs, mechanistic clarity, and potentially unparalleled opportunity for accelerating the development and wide-scale clinical use of safe, effective, regulatable and patient-specific therapies. The following review introduces a novel domain of anticoagulant therapy referred to as aptamers (derived from the Latin aptus - to fit), considering their history, development, and potential application in patient care arenas.

Aptamers are oligonucleotides evolved in vitro or in nature to bind target ligands with high affinity and specificity. They are emerging as powerful tools in the fields of therapeutics, drug development, target validation and diagnostics. Aptamers are attractive alternatives to antibody- and small-molecule-based therapeutics owing to their stability, low toxicity, low immunogenicity and improved safety. With the recent approval of the first aptamer drug Macugen by the US FDA, there is great impetus to develop therapeutic aptamers that can target a wide array of disease states. The recent demonstration that aptamer activity can be reversed by the administration of a simple antidote greatly enhances the potential value of aptamers as therapeutic agents.Gene Therapy (2007) 14, 283–291. doi:10.1038/sj.gt.3302900 [ABSTRACT FROM AUTHOR]