Aptamer Inhibition of von Willebrand Factor in Canine Myocardial Infarction
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Date
2020-05
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The Ohio State University
Abstract
Heart disease is the leading cause of death for both men and women worldwide. With this project, we propose a new therapy to provide a safer and more effective thrombolytic for patients who suffer an MI. von Willebrand Factor (VWF) is a known mediator in platelet adhesion and aggregation. We have developed an RNA aptamer which acts to directly inhibit von Willebrand Factor. This aptamer, named DTRI-031, can be reversed with an antidote oligonucleotide, DTRI-025, that was specifically developed to rapidly and durably reverse DTRI-031 function. Previous studies in this laboratory have demonstrated that DTRI-031 resulted in decreased infarct sizes after stroke and decreased platelet reactivity after vascular injury in canines. Our current study will first attempt to modify a large animal model of porcine myocardial infarction (MI) for canine utilization. Once our canine MI model is characterized, we will attempt to demonstrate the ability of DTRI-031 to maintain cardiac function and platelet reactivity after MI compared to vehicle control. We will utilize cardiac magnetic resonance imaging (MRI) to measure ejection volume, stroke volume, and cardiac output. We will stain hearts with Evan’s Blue after MI to compare infarct size. Lastly, we will monitor platelet reactivity utilizing whole blood aggregometry before MI, during ischemia, and at time of sacrifice in addition to measurement of plasma VWF levels. Heart rate, body temperature, and blood pressure monitoring ensure physiological conditions are maintained throughout the surgical procedures. We anticipate that the canine MI model will be characterized rapidly with little modification from the previously published porcine model and that DTRI-031 will result in less infarction and retain greater cardiac function. This is an ongoing experiment.
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Keywords
aptamer, myocardial infarction, thrombolytic, canine, heart