AAV vector development, back to the future

Abstract

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 crucial role in vector transduction efficiency and host adaptation. An assessment of past and present clinical trials as well as future directions is provided to illustrate the field's trajectory. Finally, another unique milestone in AAV research is also reported; namely, a pool of AAV libraries has been successfully administered to human decedents and analyzed, representing a transformative step in AAV evolution and selection for human applications. These studies should pave the way for more refined AAV vector optimization, accelerating the development of next-generation gene therapies with enhanced clinical translatability, potentially accelerating the gene therapy revolution.

Keywords: AAV; AAV library; ITR; directed evolution; gene therapy; human decedent; rational design; viral vectors.