Engineered bacterial voltage-gated sodium channel platform for cardiac gene therapy

In this in vitro, in silico, and in vivo study Nguyen and colleagues show that specific and stable viral gene delivery of engineered prokaryotic voltage-gated sodium channels (BacNav) to cardiomyocytes can directly augment cardiac tissue excitability and conduction. 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(v)) 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(v) significantly reduces occurrence of conduction block and reentrant arrhythmias in fibrotic cardiac cultures. Moreover, functional BacNa(v) 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(v)-based gene therapies for cardiac conduction disorders.

Automated summary

This study demonstrates that introducing engineered prokaryotic voltage-gated sodium channels (BacNav) can enhance excitability and conduction in cardiomyocytes, potentially providing a new approach for treating cardiac arrhythmias. The use of small-sized, codon-optimized BacNav channels significantly improves excitability and conduction in rat and human cardiomyocytes, as well as adult cardiac tissues from different species. Additionally, the expression of BacNav reduces the occurrence of conduction block and reentrant arrhythmias in fibrotic cardiac cultures, without causing any adverse effects on cardiac electrophysiology in mice.