Department of Biomedical Engineering, Duke University, Durham, NC, USA.
Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
Nat Commun. 2022 Feb 2;13(1):620. doi: 10.1038/s41467-022-28251-6.
Therapies for cardiac arrhythmias could greatly benefit from approaches to enhance electrical excitability and action potential conduction in the heart by stably overexpressing mammalian voltage-gated sodium channels. However, the large size of these channels precludes their incorporation into therapeutic viral vectors. Here, we report a platform utilizing small-size, codon-optimized engineered prokaryotic sodium channels (BacNa) driven by muscle-specific promoters that significantly enhance excitability and conduction in rat and human cardiomyocytes in vitro and adult cardiac tissues from multiple species in silico. We also show that the expression of BacNa significantly reduces occurrence of conduction block and reentrant arrhythmias in fibrotic cardiac cultures. Moreover, functional BacNa channels are stably expressed in healthy mouse hearts six weeks following intravenous injection of self-complementary adeno-associated virus (scAAV) without causing any adverse effects on cardiac electrophysiology. The large diversity of prokaryotic sodium channels and experimental-computational platform reported in this study should facilitate the development and evaluation of BacNa-based gene therapies for cardiac conduction disorders.
心脏心律失常的治疗可以从通过稳定过表达哺乳动物电压门控钠通道来增强心脏的电兴奋性和动作电位传导的方法中受益。然而，这些通道的体积较大，无法将其纳入治疗性病毒载体。在这里，我们报告了一个利用小尺寸、密码子优化的工程原核钠通道（BacNa）的平台，该平台由肌肉特异性启动子驱动，可显著增强大鼠和人心肌细胞以及多种物种的成年心脏组织的体外兴奋性和传导性。我们还表明，BacNa 的表达可显著减少纤维化心脏培养物中传导阻滞和折返性心律失常的发生。此外，静脉注射自互补腺相关病毒（scAAV）六周后，功能性 BacNa 通道在健康小鼠心脏中稳定表达，而不会对心脏电生理学产生任何不良影响。本研究报告的大量原核钠通道和实验计算平台应有助于开发和评估基于 BacNa 的心脏传导障碍基因治疗方法。
