Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels

Abstract

Endothelial surface and circulating glycoprotein von Willebrand factor (vWF) regulates platelet adhesion and is associated with thrombotic diseases, including ischemic stroke, myocardial infarction, and peripheral vascular disease. Thrombosis, as manifested in these diseases, is the leading cause of disability and death in the western world. Current parenteral antithrombotic and thrombolytic agents used to treat these conditions are limited by a short therapeutic window, irreversibility, and major risk of hemorrhage. To overcome these limitations, we developed a novel anti-vWF aptamer, called DTRI-031, that selectively binds and inhibits vWF-mediated platelet adhesion and arterial thrombosis while enabling rapid reversal of this antiplatelet activity by an antidote oligonucleotide (AO). Aptamer DTRI-031 exerts dose-dependent inhibition of platelet aggregation and thrombosis in whole blood and mice, respectively. Moreover, DTRI-031 can achieve potent vascular recanalization of platelet-rich thrombotic occlusions in murine and canine carotid arteries. Finally, DTRI-031 activity is rapidly (<5 min) and completely reversed by AO administration in a murine saphenous vein hemorrhage model, and murine toxicology studies indicate the aptamer is well tolerated. These findings suggest that targeting vWF with an antidote-controllable aptamer potentially represents an effective and safer treatment for thrombosis patients having plateletrich arterial occlusions in the brain, heart, or periphery.

Platelets as Modulators of Cerebral Ischemia/Reperfusion Injury

“…Although the anti-vWF nanobody caplacizumab was initially approved in 2018 as treatment for thrombotic thrombocytopenic purpura (47), it was also shown to be an effective therapy in a stroke model using guinea pigs (48), indicating that it might also be beneficial in stroke therapy. One additional promising feature of strategies targeting the GPIb-vWF axis is that they have been shown to exert thrombolytic activity (48–50). Thus, in addition to dampening thrombo-inflammation (22, 51), also the recurrence of stroke-causing thrombi might be reduced.…”

A Mini-Review: Clinical Development and Potential of Aptamers for Thrombotic Events Treatment and Monitoring

“…Nimjee et al recently developed a new anti-VWF RNA aptamer named DTRI-031 [24]. This aptamer was truncated to a 30-mer from the original 60-mer candidate aptamer.…”

“…Additionally, DTRI-03 was able to induce vascular recanalization in mouse and dog carotid arteries. The antidote oligonucleotide was also able to reverse the antiplatelet and anticoagulation effects of DTRI-031 [24].…”

Attack on stroke

“…A 2019 study shows that their drug, Aptamer DTRI-031, inhibited platelet aggregation in vitro, and was able to destroy a formed blood clot in mice and dogs at a much higher rate than the standard 'clot buster' drug tPA 1 . What's more, the team developed an antidote able to reverse the effects of DTRI-031, significantly reducing the risk of haemorrhage, compared with tPA.…”