In vivo gene therapy with adeno-associated viral (AAV) vectors is holding its promise for treatment of genetic diseases, yet some challenges remain that prevent to expand this approach to a larger patient population. These include: AAV cargo capacity limited to about 5 kb which prevents their application to conditions due to mutations in genes with a larger coding sequence; the episomal status of AAV genomes which results in short-term expression in proliferating tissues; efficient approaches to target toxic gain-of-function mutations that do not benefit from traditional gene addition. To overcome these limitations, we have developed platforms based on the co-delivery of 2 AAV vectors that either EXPand AAV transfer capacity or EDIT genomic loci by stably integrating therapeutic donor DNAs. We provide proof-of-concept of the efficacy and safety of these approaches in animal models of human inherited diseases.