Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels
| Autor: | Jenna Wilson, Debra G Wheeler, Laura J. Sommerville, David Dornbos, Kendyl Carlisle, Nicholas Venetos, Richard C. Becker, Shahid M Nimjee, Juliana M. Layzer, George A. Pitoc, Nicholas Musgrave, Allyson Huttinger, Spencer Talentino, Shoeb I. Khan, Holly Moody, Bruce A. Sullenger, Jay L. Zweier, Camille Bratton, Rachel E. Rempel, Matthew Joseph, Maureane Hoffman, Cheyenne Jones |
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| Rok vydání: | 2019 |
| Předmět: |
Blood Platelets
Male medicine.medical_specialty Platelet Aggregation Antidotes Drug Evaluation Preclinical Oligonucleotides Arterial Occlusive Diseases Mice 03 medical and health sciences Dogs Platelet Adhesiveness 0302 clinical medicine Fibrinolytic Agents Von Willebrand factor Internal medicine von Willebrand Factor Drug Discovery Antithrombotic Genetics Animals Humans Medicine Platelet Myocardial infarction Molecular Biology Stroke 030304 developmental biology Whole blood Pharmacology 0303 health sciences Dose-Response Relationship Drug biology business.industry Vascular disease Thrombosis Aptamers Nucleotide medicine.disease Healthy Volunteers Mice Inbred C57BL 030220 oncology & carcinogenesis Cardiology biology.protein Molecular Medicine Original Article Female Carotid Artery Injuries business |
| Zdroj: | Mol Ther |
| ISSN: | 1525-0016 |
| DOI: | 10.1016/j.ymthe.2019.03.016 |
| Popis: | Endothelial surface and circulating glycoprotein von Willebrand factor (vWF) regulates platelet adhesion and is associated with thrombotic diseases, including ischemic stroke, myocardial infarction, and peripheral vascular disease. Thrombosis, as manifested in these diseases, is the leading cause of disability and death in the western world. Current parenteral antithrombotic and thrombolytic agents used to treat these conditions are limited by a short therapeutic window, irreversibility, and major risk of hemorrhage. To overcome these limitations, we developed a novel anti-vWF aptamer, called DTRI-031, that selectively binds and inhibits vWF-mediated platelet adhesion and arterial thrombosis while enabling rapid reversal of this antiplatelet activity by an antidote oligonucleotide (AO). Aptamer DTRI-031 exerts dose-dependent inhibition of platelet aggregation and thrombosis in whole blood and mice, respectively. Moreover, DTRI-031 can achieve potent vascular recanalization of platelet-rich thrombotic occlusions in murine and canine carotid arteries. Finally, DTRI-031 activity is rapidly ( |
| Databáze: | OpenAIRE |
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