Abstract WP99: Reversible VWF Inhibitor Reduces Stroke Volumes Compared to TPA in Canine Model of Large Vessel Occlusion Stroke

Abstract

Introduction: Von Willebrand Factor (VWF) is a glycoprotein critical to initiate, propagate and stabilize an occlusive thrombus seen in a significant segment of large vessel occlusion stroke as well as during neuroendovascular procedures, which approach 15% despite using heparin. Recombinant tissue plasminogen activator (rtPA) is the only drug approved to treat ischemic stroke despite poor recanalization rates (~10%), significant risk of intracranial hemorrhage and lack of reversibility. Hypothesis: An antidote-controlled RNA aptamer targeting VWF will significantly reduce stroke volume in a canine model of large vessel occlusion (LVO) stroke. Methods: We developed an RNA aptamer DTRI-031 and a matched reversal agent. A canine model of basilar artery occlusion (BAO) stroke was used to assess DTRI-031 efficiency in thromboembolic stroke compared to rtPA and vehicle control in vivo. Laser speckle imaging (LSI) and digital subtraction angiography (DSI) was used to study the microvasculature after BAO and subsequent treatment with DTRI-031, rtPA or negative control. Magnetic resonance imaging (MRI) was used to assess stroke volume and platelet aggregometry was used to assess platelet function during the experiment. Results: Botrocetin-induced aggregometry demonstrated >95% inhibition compared to rtPA and negative control (p<0.0001) (n=6 per group). Laser speckle imaging demonstrated improved revascularization and MRI demonstrated the lowest stroke volume in DTRI-031-treated dogs compared to rtPA and negative control (p<0.05). Conclusions: DTRI-031 demonstrated superior recanalization, reduced stroke burden and robust platelet inhibition in the setting of LVO stroke compared to rtPA. These findings suggest that this drug-antidote combination targeting VWF may represent a superior treatment paradigm in stroke ischemic stroke and as well as in acute thrombosis in neurointerventional procedures.