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 painting in New Zealand white rabbits.
复制标题
Ad-KCNH2-G628S 通过新西兰白兔心房涂敷给药的临床前安全性和生物分布评估。
DOI：
10.1111/bcpt.13885
复制
发表时间：
2023
影响因子：
3.1
通讯作者：
Donahue,JKevin
中科院分区：
文献类型：
--
作者：
Benson,JanetM;Wang,Gensheng;Hutt,JulieA;Wu,Guodong;Kaminsky,StephenM;Cram,Sara;Barur,Rajeshkumar;Donahue,JKevin
术后心房颤动（POAF）是心脏手术后最常见的并发症。尽管实施了几种药理学策略，POAF的发生率仍保持在约30%。在这项临床前研究中，将1.5 × 1010或1.5 × 1012Ad‐KCNH2‐G628S载体颗粒（vp）应用于新西兰大白兔心房心外膜或1.5 × 1012vp应用于整个心外膜表面。生理盐水和载体载体作为程序对照。这些动物被跟踪了长达42天。载体基因组在心房中持续存在长达42天，没有分布到胸外器官。在标准毒理学终点、血压、左心房或心室射血分数、心电图参数、血清IL - 6或肌钙蛋白浓度方面，没有可归因于试验品的不良反应。在第7天和第21天观察到低剂量而非高剂量动物心房游离壁心肌的单核浸润，但这些变化没有持续或影响心功能。在按心脏大小进行缩放后，结果表明，在人体临床试验建议的最大剂量的25倍下，测试品是安全的。
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 × 1010or 1.5 × 1012Ad‐KCNH2‐G628S vector particles (vp) were applied to the atrial epicardium or 1.5 × 1012vp 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.