Poster abstracts
Poster number 47 submitted by Shahid Nimjee
Reversible Aptamer Inhibition of Von Willebrand Factor is a Potent Thrombolytic and Ameliorates Stroke Burden Following Vascular Injury Compared to Recombinant Tissue Plasminogen Activator
David Dornbos III, Debra G. Wheeler, Allyson Huttinger, (Department of Neurological Surgery), Hallie Harris, Surya Gnyawali, (Department of Surgery), Cameron Rink, Chandan K. Sen (Department of Surgery), Nicholas Venetos, Spencer Talentino, Nicholas Musgrave (Department of Neurological Surgery), Cheyenne Jones (Department of Neurological Surgery), Jay Zweier (Department of Medicine)
Abstract:
Introduction: While recombinant tissue plasminogen activator (rTPA) is the mainstay of ischemic stroke treatment, few patients are eligible for treatment, and recanalization is only seen in 25-50%. Von Willebrand Factor (VWF) inhibition may play a role in thrombolyis.
Hypothesis: VWF inhibition with an RNA aptamer lyses arterial thrombus and decreases ischemic injury. Furthermore, aptamer reversal with an antidote oligonucleotide ameliorates intracranial hemorrhage (ICH).
Methods: Adult wild-type (C57BL/6J) mice were anesthetized, and the right carotid artery was exposed. Baseline carotid flow was obtained using a Doppler flow probe, and thrombotic occlusion was induced with a ferric chloride patch. After clot stabilization, mice were administered vehicle (platelet binding buffer, n=11), no infusion (n=8), rTPA (n=5) or VWF aptamer (n=5). Carotid flow was monitored for an additional 100 minutes. In a second cohort of mice, a 6-0 nylon suture was advanced within the carotid artery to generate vascular injury and ICH. Mice were given vehicle (n=16), rTPA (n=11), VWF aptamer (n=9) or aptamer/antidote (n=8). An MRI was obtained after 90 minutes to assess stroke and ICH volumes.
Results: VWF aptamer successfully restored carotid blood flow 45 minutes following carotid occlusion (Figure 1) compared to controls (p<0.01*) and rTPA (p<0.05+). Stroke volume was significantly decreased in mice treated with VWF aptamer (23.03 ± 6.81 mm3) and aptamer/antidote (12.48 ± 5.68 mm3) compared to vehicle (45.25 ± 4.14 mm3, p<0.01). ICH volumes in mice treated with rTPA (2.64 ± 0.84 mm3) were trending higher than vehicle (1.51 ± 0.17 mm3), VWF aptamer (1.92 ± 0.22 mm3) or aptamer/antidote (1.31 ± 0.35 mm3).
Conclusions: Aptamer inhibition of VWF is a potent thrombolytic agent with greater efficacy compared to rTPA. VWF inhibition appears safe with a trend toward lower ICH volumes in animals treated with aptamer and aptamer/antidote compared to rTPA.
Keywords: thrombosis, aptamer, antidote oligonucleotide