Reversible VWF Inhibitor reduces stroke volumes to rTPA in canine model of large vessel occlusion stroke
Debra Wheeler, Caitlin Hatten, Matthew Joseph, Shahid Nimjee, Ian Mandybur, Allyson Huttinger, Surya Gnyawali, Cole Anderson
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 and during endovascular neurosurgical 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.
Objective: Compare an antidote-controlled RNA aptamer targeting VWF to rtPA in a canine model of large vessel occlusion (LVO) stroke.
Methods: We developed an RNA aptamer DTRI-031 and a matched reversal agent. Canine model of basilar artery occlusion (BAO) stroke was used to assess DTRI-031 efficacy 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 of 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 a drug-antidote combination targeting VWF may represent a superior drug-antidote regimen in stroke and acute cerebral thrombosis in during endovascular neurosurgical procedures.