Current and Emerging Issues in Adeno-Associated Virus Vector-Mediated Liver-Directed Gene Therapy.

Adeno-associated virus (AAV) vectors have demonstrated safety and efficacy for gene transfer to hepatocytes in preclinical models, in various clinical trials and from a clinical experience with a growing number of approved gene therapy products. Although the exact duration is unknown, the expression of therapeutic genes in hepatocytes remains stable for several years after a single administration of the vector at clinically relevant doses in adult patients with hemophilia and other inherited metabolic disorders. However, clinical applications, especially for diseases requiring high AAV vector doses by intravenous administrations, have raised several concerns. These include the high prevalence of pre-existing immunity against the vector capsid, activation of the complement and the innate immunity with serious life-threatening complications, elevation of liver transaminases, liver growth associated with loss of transgene expression, underlying conditions negatively affecting AAV vector safety and efficacy. Despite these issues, the field is rapidly advancing with a better understanding of vector-host interactions and the development of new strategies to improve liver-directed gene therapy. This review provides an overview of the current and emerging challenges for AAV-mediated liver-directed gene therapy.