Aptamer-Based von Willebrand Factor Inhibition Mediates Platelet and Neutrophil Activation in Canine Middle Cerebral Artery Occlusion
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Date
2023-05
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The Ohio State University
Abstract
Acute ischemic stroke (AIS) is a leading cause of combined death and disability that has seen a 70% increase in incidence since 19901. Current treatment includes mechanical thrombectomy or administration of recombinant tissue plasminogen activator (rTPA). rTPA activates plasminogen, recruiting plasmin to break down fibrin within a clot2. However, rTPA is limited due to its short administration window and risk of hemorrhage, leaving around 85% of AIS patients without sufficient treatment3.
Von Willebrand Factor (VWF) is a glycoprotein highly implicated in pathological thrombosis following vascular injury. Due to its role in platelet adhesion, aggregation, and clot contraction, VWF is a compelling target for AIS treatment. BB-031 is an aptamer targeted to inhibit VWF with high specificity (Oney et al. 2007, Nimjee et al. 2012, Nimjee et al. 2019). Additionally, the effects of BB-031 can be rapidly reversed upon administration of its targeted antidote, BB-025, minimizing the hemorrhage risk characteristic of rTPA (Oney et al. 2007, Nimjee et al 2012).
In the following studies, we simulated middle cerebral artery occlusion (MCAO) over a period of 6 hours in canine hounds to assess the efficacy of varied dosages of BB- 031, as the MCA is the most prevalent location for clinical stroke4. Performance was assessed from multiple parameters including platelet inhibition, infarct volume, and cerebral reperfusion, resulting in 0.5 mg/kg as an optimal concentration. We also assessed the ability of BB-025 to reverse BB-031 activity. More recent studies aim to further understand the inflammatory profile of MCAO in the presence of BB-031, as long- term inflammation remains a pervasive challenge in stroke care. We expect 0.5 mg/kg of BB-031 will significantly reduce inflammatory markers implicated in AIS due to its role in attenuating platelet activation and aggregation.
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Keywords
neurological surgery, stroke, translational research, vascular medicine