Electroporation-mediated delivery of functional genes – a promising approach for non-viral-based gene therapy of the failing heart

Background: Gene therapy represents a promising strategy for the treatment of heart failure (HF). Mostly, applied vectors such as replicant free viruses, show serious adverse effects (host immune reactions, cancer development). Electroporation may present an approach to overcome these shortcomings. Given the down-regulation of the β-adrenergic receptor signaling in HF, the current project studied the viral-free transfection of the β-adrenergic receptor kinase inhibitor (βARKct) in skeletal and myocardial muscles in vivo by electroporation.

Methods: HF was induced in 15 rats by LAD coronary ligation. After three weeks, LV-function was evaluated by echocardiography. Electroporation was performed on the beating heart and simultaneously in a peripheral muscle. Transfection was performed with βARKct and a reporter plasmid as a control (n=3). Three, five, and seven days post-intervention, expression was assessed by semi-quantitative immunohistology and Western blot.

Results: Electroporation was technically easy to apply and safe. Serial assessment of gene expression demonstrated intramyocardial expression of βARKct. Expression pattern showed strongest expression areas around electrode placement zones. By using a ubiquitin promoter, strong expression of βARKct was maintained up to seven days.

Conclusion: Electroporation is a promising therapeutic approach for non-viral-based gene therapy for HF. It is easy to apply, without harmful side-effects, and results in a long-term expression. Further functional analysis is necessary to confirm the positive effects of restoring the long-term β-adrenergic signaling for improvement of HF.