Translating Nucleic Acid Aptamers to Antithrombotic Drugs in Cardiovascular Medicine

Nucleic acid aptamers offer several distinct advantages for the selective inhibition of protein targets within the coagulation cascade. A highly attractive feature of aptamers as antithrombotics is their ability to encode for complementary "controlling agents" which selectively bind to and neutralize their active counterparts via Watson-Crick base pairing or, in a less selective and clinically characterized manner, cationic polymers that can counteract the activity of an aptamer or free/protein-complexed nucleic acid. The former property allows aptamer-based antithrombotic therapies to be administered with a goal of selective, high intensity target inhibition, knowing that rapid drug reversal is readily available. In addition, by purposefully varying the ratio of active agent to a specific controlling agent administered, the intensity of antithrombotic therapy can be regulated with precision according to patient needs and the accompanying clinical conditions. REG1, currently undergoing phase 2B clinical investigation, consists of an RNA aptamer (RB006; pegnivacogin) which targets factor IXa and its complementary controlling agent (RB007; anivamersen). Aptamers directed against other serine coagulation proteases, some with and some without parallel controlling agents, have been designed. Aptamers directed against platelet surface membrane receptor targets are in preclinical development. The following review offers a contemporary summary of nucleic acid aptamers as a translatable platform for regulatable antithrombotic drugs expanding the paradigm of patient- and disease-specific treatment in clinical practice.