The Cold Case Files of rAAV Capsid Influence on Transduction: New Leads

Adeno-associated virus (AAV) is a prevalent vector in viral gene therapy. Given its importance, significant efforts focus on engineering the capsid residues on the exterior surface to increase cell/tissue-specific binding to cellular receptors or to decrease immunogenicity. But there is also a need for stable transgene expression to achieve the desired therapeutic effect. For rAAV transgene regulation, all approaches to date utilize sequence elements within the transgene cassette to restrict the localization and level of transgene expression. However, there is accumulating evidence that rAAV transgene expression can be mediated by rAAV capsid residues distinct from cell receptor binding residues, but these reports have largely gone 'cold' due to a lack of a clear mechanism. Thus, these novel rAAV capsid elements may revise interpretation of both past and future rAAV capsid engineering. This review will coalesce the data supporting this novel rAAV capsid role and describe how the capsid influences transgene expression with a focus on interactions with the transgene, binding cellular proteins, and epigenetic modulation.