Inhibition of the Glycoprotein Von Willebrand Factor via an RNA Aptamer in a Large Animal Model of Middle Cerebral Arterial Occlusion Stroke

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The Ohio State University

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Every three and a half minutes an individual dies from a stroke. Approximately 85% of strokes are ischemic, and over half of all ischemic strokes originate in the middle cerebral artery (MCA)1-2,6. Currently, standard stroke treatment includes intravenous infusion of recombinant tissue plasminogen activator (rTPA), a serine protease that's primary function is to eliminate occlusion caused by blood clots via thrombolysis3. This method is only marginally effective at thrombolysis, cannot be reversed, and must be given within a timeframe of 3-4.5 hours of stroke onset, due to increased hemorrhage risk. Knowing that von Willebrand Factor (vWF), a known glycoprotein mediator in platelet adhesion and aggregation, plays a major role in vessel injury hemostasis, the Nimjee Lab developed a vWF-inhibiting aptamer, DTRI-031 (REF Oney, Nimjee et al. Oligonucleotides 2007; Nimjee et al. Molecular Therapy 2012 and Nimjee et al. Molecular Therapy 2019). Aptamers are RNA or DNA oligonucleotides which bind to and inhibit specific target molecules (REF Nimjee et al. Annual Reviews of Medicine 2005). In this study, we tested the hypothesis that DTRI-031 can lyse a blood clot 6 hours after it is placed in the MCA of canine hounds4. Furthermore, DTRI-031 can be rapidly reversed by another single-stranded RNA ligand, DTRI-025, to mitigate hemorrhage risk induced by the activity of DTRI-031. This study aims to demonstrate the efficacy of DTRI-031 to thrombolyse an occlusive thrombus in a large animal MCA occlusion (MCAO) model by measuring functional differences at different aptamer concentrations, like reperfusion rate, infarct volume, and inhibition of platelet activity and aggregation. Additionally, this study aims to demonstrate the reversibility of DTRI-031 by DTRI-025 using a point-of-care platelet activity assay (PFA-100) and platelet aggregometry. We anticipate that higher concentrations of DTRI-031 will result in improved cerebral perfusion, decreased infarct size, and lower platelet aggregation. Moreover, DTRI-025 will rapidly and durably reverse DTRI-031 functionality in both platelet activity and aggregation assays.



Stroke, Aptamer, MCAO, Biomedical, Engineering, Neurosurgery