Myocardial infarction creates a critical time window for AAV-based cardiac gene transfer

Approaches to enhance adeno-associated virus (AAV)-based cardiac gene transfer are the key to successful cardiac gene therapy, but factors influencing AAV transduction remain poorly investigated. This study showed that myocardial infarction (MI) enhanced cardiac AAV transduction, peaking at the third day post-MI in mice. The excessive AAV enrichment at the border zone is due to local vascular permeabilization and cardiomyocyte metabolic remodeling, which is independent of AAV dosage, serotypes and promoters. This effect was harnessed to boost cardiac base editing and improve the outcome of gene therapy for MI in mice. Thus, heart disease itself is a non-negligible factor that alters AAV-based cardiac gene transfer, which provides a new inroad to develop approaches to enhance cardiac gene therapy.