AAV vector development, back to the future

Adeno-associated virus (AAV) has become a pivotal tool in gene therapy, providing a safe and efficient platform for long-term transgene expression. This review presents a comprehensive analysis of AAV's historical development, from its initial identification as a "contaminant" to its current clinical applications. We examine the molecular evolution of AAV, detailing advancements in vector engineering, rational design, directed evolution platforms, and computational modeling, which have expanded its therapeutic potential across diverse disease areas. Additionally, we explore AAV genome regulation, with a particular focus on inverted terminal repeats (ITRs) and AAV capsid-genome interactions, which play a…