An all-in-one AAV vector for cardiac-specific gene silencing by an adenine base editor

Abstract

ABE editing outcomes are highly variable and unpredictable, depending on various factors. Therefore, the success rate of creating targeted A*T-to-G*C conversions using ABE is not high. But utilizing ABE to target RNA splicing sites for gene silencing has a higher success rate. Another challenge for base editing in the heart is that traditional ABE is too large in size, necessitating dual AAV delivery. Whether single AAV delivery can be achieved remains to be explored. In this study, we demonstrated how the diversity of Cas9 homologs and screening of sgRNAs can facilitate cardiac base editing. Single-AAV base editing outperformed dual-AAV systems in the heart, potentially benefiting from chromatin accessibility-guided sgRNA selection. These findings have important implications for the development of more effective and predictable base editing tools for cardiac gene therapy.