Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels.

Abstract

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 (<5 min) and completely reversed by AO administration in a murine saphenous vein hemorrhage model, and murine toxicology studies indicate the aptamer is well tolerated. These findings suggest that targeting vWF with an antidote-controllable aptamer potentially represents an effective and safer treatment for thrombosis patients having platelet-rich arterial occlusions in the brain, heart, or periphery.

• Authors: Shahid M Nimjee, David Dornbos 3rd, George A Pitoc, Debra G Wheeler, Juliana M Layzer, Nicholas Venetos, Allyson Huttinger, Spencer E Talentino, Nicholas J Musgrave, Holly Moody, Rachel E Rempel, Cheyenne Jones, Kendyl Carlisle, Jenna Wilson, Camille Bratton, Matthew E Joseph, Shoeb Khan, Maureane R Hoffman, Laura Sommerville, Richard C Becker, Jay L Zweier, Bruce A Sullenger
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 27 Issue 7 Pg. 1228-1241 (07 03 2019) ISSN: 1525-0024 [Electronic] United States
• PMID: 30987839 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019. Published by Elsevier Inc.

Chemical References

• Antidotes
• Aptamers, Nucleotide
• Fibrinolytic Agents
• Oligonucleotides
• von Willebrand Factor

Topics

• Animals
• Antidotes (pharmacology)
• Aptamers, Nucleotide (chemical synthesis, metabolism, pharmacology)
• Arterial Occlusive Diseases (drug therapy)
• Blood Platelets (drug effects, metabolism)
• Carotid Artery Injuries (drug therapy)
• Dogs
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Female
• Fibrinolytic Agents (pharmacology)
• Healthy Volunteers
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Oligonucleotides (pharmacology)
• Platelet Adhesiveness (drug effects)
• Platelet Aggregation (drug effects)
• Thrombosis (drug therapy, prevention & control)
• von Willebrand Factor (antagonists & inhibitors, metabolism)