Key result
Epicardial Ad-KCNH2-G628S gene painting shows no adverse cardiac toxicity at up to ~25-fold human doses.
Why the study?
Post-operative atrial fibrillation remains common despite pharmacological strategies, motivating preclinical safety and biodistribution assessment of an adenoviral gene therapy vector encoding KCNH2-G628S.
Does Ad-KCNH2-G628S administered via epicardial painting have a safe toxicity and biodistribution profile in a healthy rabbit model?
Does Ad-KCNH2-G628S administered via epicardial painting have a safe toxicity and biodistribution profile in a healthy rabbit model?
Epicardial painting of the Ad-KCNH2-G628S vector demonstrated an acceptable safety and biodistribution profile in rabbits, supporting advancement toward clinical trials for postoperative atrial fibrillation.
Supports progression to first-in-human trials for postoperative AF gene therapy; leaves open clinical safety and efficacy confirmation.
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 × 10 10 or 1.5 × 10 12 Ad‐KCNH2‐G628S vector particles (vp) were applied to the atrial epicardium or 1.5 × 10 12 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.
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Benson et al. (2023) studied Healthy (Preclinical model for postoperative atrial fibrillation prevention) (n=121). Ad-KCNH2-G628S adenovirus vector vs. Saline and vector vehicle was evaluated on Safety (adverse effects on standard toxicological endpoints, hemodynamics, cardiac function, and electrocardiography) and vector biodistribution. Ad-KCNH2-G628S epicardial gene painting showed no adverse effects on standard toxicological endpoints, cardiac function, or electrocardiography in rabbits at doses up to 25 times the maximum proposed human dose.
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