Aptamers as Rapid Onset and Rapidly Reversible Antithrombotic Agents
Clinical evaluation of our factor IXa RNA aptamer in two thousand patients undergoing percutaneous coronary intervention has demonstrated that aptamers can rapidly and potently inhibit their target proteins in patients and that antidote molecules can rapidly and precisely control such activity in the minute time frame. These observations suggest that aptamers represent useful molecules to tightly control biochemical processes in humans in real time. To begin to explore this potential further, we have started to evaluate the utility of antidote-mediated control of aptamers for a variety of other therapeutic and diagnostic applications. We will describe our recent progress developing a rapidly controllable factor Xa anticoagulant aptamer to effectively yet reversibly control blood coagulation during cardiopulmonary bypass surgery and a rapidly reversible VWF aptamer for improving the treatment of thrombotic stroke. We have observed that aptamers, which target exosites on coagulation factors, can complement active site inhibitors to yield potent anticoagulant regiments (Gunaratne et al., 2018) that can support circulation of blood through extracorporeal oxygenator circuits. Moreover we have observed that an aptamer targeting the A1 domain of VWF can serve as a rapid onset and rapidly reversible antithrombotic agent. This aptamer prevents platelet recruitment and can induce recanalization of occluded arteries while a matched antidote oligonucleotide can rapidly reverse such anti-platelet activity and thereby limit bleeding following vascular injury (Nimjee et al., 2019). Collectively these clinical and preclinical studies lead us to believe that rapidly controllable aptamers represent valuable therapeutic agents that will provide physicians the ability to monitor and precisely control blood coagulation, as well as other biological pathways, in real time in response to individual patients' needs.
GunaratneR, KumarS, FrederiksenJW, et al. Multimodal, antidote-controllable anticoagulation for cardiopulmonary bypass using aptamer-drug pairs. Nature Biotechnology 2018;36:606-613.
NimjeeSM, Dornbos, IIID, Pitoc GA, et al. Preclinical Development of a VWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels. Molecular Therapy. 2019;27:1228-1241.
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