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Preclinical safety and biodistribution assessment of Ad‐KCNH2‐G628S administered via atrial painting in New Zealand white rabbits

Preclinical safety and biodistribution assessment of Ad‐KCNH2‐G628S administered via atrial... Post‐operative atrial fibrillation (POAF) is the most common complication after cardiac surgery. Despite implementation of several pharmacological strategies, incidence of POAF remains at approximately 30%. An adenovirus vector encoding KCNH2‐G628S has proven efficacious in a porcine model of AF. In this preclinical study, 1.5 × 1010 or 1.5 × 1012 Ad‐KCNH2‐G628S vector particles (vp) were applied to the atrial epicardium or 1.5 × 1012 vp were applied to the whole epicardial surface of New Zealand White rabbits. Saline and vector vehicle served as procedure controls. Animals were followed for up to 42 days. Vector genomes persisted in the atria up to 42 days, with no distribution to extra‐thoracic organs. There were no adverse effects attributable to test article on standard toxicological endpoints or on blood pressure, left atrial or ventricular ejection fractions, electrocardiographic parameters, or serum IL‐6 or troponin concentrations. Mononuclear infiltration of the myocardium of the atrial free walls of low‐dose, but not high‐dose animals was observed at 7 and 21 days, but these changes did not persist or affect cardiac function. After scaling for heart size, results indicate the test article is safe at doses up to 25 times the maximum proposed for the human clinical trial. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Basic & Clinical Pharmacology & Toxicology Wiley

Preclinical safety and biodistribution assessment of Ad‐KCNH2‐G628S administered via atrial painting in New Zealand white rabbits

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References (30)

Publisher
Wiley
Copyright
© 2023 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd
ISSN
1742-7835
eISSN
1742-7843
DOI
10.1111/bcpt.13885
Publisher site
See Article on Publisher Site

Abstract

Post‐operative atrial fibrillation (POAF) is the most common complication after cardiac surgery. Despite implementation of several pharmacological strategies, incidence of POAF remains at approximately 30%. An adenovirus vector encoding KCNH2‐G628S has proven efficacious in a porcine model of AF. In this preclinical study, 1.5 × 1010 or 1.5 × 1012 Ad‐KCNH2‐G628S vector particles (vp) were applied to the atrial epicardium or 1.5 × 1012 vp were applied to the whole epicardial surface of New Zealand White rabbits. Saline and vector vehicle served as procedure controls. Animals were followed for up to 42 days. Vector genomes persisted in the atria up to 42 days, with no distribution to extra‐thoracic organs. There were no adverse effects attributable to test article on standard toxicological endpoints or on blood pressure, left atrial or ventricular ejection fractions, electrocardiographic parameters, or serum IL‐6 or troponin concentrations. Mononuclear infiltration of the myocardium of the atrial free walls of low‐dose, but not high‐dose animals was observed at 7 and 21 days, but these changes did not persist or affect cardiac function. After scaling for heart size, results indicate the test article is safe at doses up to 25 times the maximum proposed for the human clinical trial.

Journal

Basic & Clinical Pharmacology & ToxicologyWiley

Published: Aug 1, 2023

Keywords: Ad‐KCNH2‐G628S; epicardial administration; post‐operative atrial fibrillation; preclinical; rabbits

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