Nucleic acid aptamers as antithrombotic agents: Opportunities in extracellular therapeutics

Abstract

SummaryAntithrombotic therapy for the acute management of thrombotic disorders has been stimulated and guided actively by our current understanding of platelet biology, coagulation proteases, and vascular science. A translatable platform for coagulation, based soundly on biochemistry, enzymology and cellular events on platelets and tissue factor-baring cells, introduces fundamental constructs, mechanistic clarity, and an unparalleled opportunity for accelerating the development and

Modulation of the Coagulation Cascade Using Aptamers

“…Modeled after ARC183, this 26-nucleotide aptamer produced a dose dependent increase of clinical coagulation assays during phase I testing in healthy male volunteers. Since this aptamer has a short half-life, after terminating infusion of Nu172, coagulation values quickly returned to baseline without requiring the use of an antidote 29 .…”

“…Use of the aptamer-antidote system in a one-hour, neonatal porcine cardiopulmonary bypass surgery model was as effective as using heparin and protamine for reversible anticoagulation 40 . Overall, these preclinical studies established the FIXa aptamer-antidote pair to be a predictable and nontoxic reversible anticoagulation system, and the two compounds (aptamer and antidote) were optimized for clinical studies as the REG1 Anticoagulation System (Regado Biosciences, Durham, NC) 29 .…”

“…No rebound anticoagulation was seen over 72 hours, indicating that the aptamer/antidote complex was stable with irreversible binding of aptamer to antidote. While clearance of the free RB006 aptamer involves mainly intravascular and some renal mechanisms, clearance of the antidote RB007, which is not formulated with a PEG, is achieved by rapid renal filtration, allowing for the re-administration of aptamer with immediate restoration of anticoagulant effects 16, 29 . Across these phase I studies, no major bleeding events or serious adverse side effects were seen with REG1 use.…”

“…Additionally, several aptamers targeting VWF have been developed 64, 65 , and the aptamer ARC1779 advanced in clinical trials for acute coronary syndromes, von Willebrand disease (VWD), and thrombotic thrombocytopenic purpura, among other indications (Table 2) 66–68 . The development, mechanisms, and clinical trials of the VWF aptamer have been reviewed extensively elsewhere 6, 29, 69, 70 , and we refer the reader to the cited literature for additional discussion on these aptamers.…”

Potential uses of G-quadruplex-forming aptamers

“…TBA was among the first aptamers to be specially developed for medical application in 1992 and could eventually replace heparin as a new type of anticoagulant; as was mentioned above, TBA specifically binds to the fibrinogen binding site at thrombin thereby inhibiting fibrinogen cleavage (see Becker et al 2010 …”