Safety of in vivo gene therapy in children: mechanisms and management of liver injury.

Gene therapies based on recombinant adeno-associated viruses (rAAVs) are radically changing the disease course of several inherited disorders with historically few treatment options. Increasing use of these therapies has revealed multiple immune-mediated adverse effects. Liver injury following systemic delivery of rAAV gene therapy is now well documented, ranging from asymptomatic liver enzyme elevations to rare cases of fatal liver failure. Most cases of severe or fatal liver failure have been reported in patients with neuromuscular disorders, who receive high systemic rAAV doses compared with patients receiving liver-targeted therapies. This Review summarises the principles of modern gene therapy and important adverse effects. We discuss mechanisms of liver injury and current uncertainties, focusing on the T cell-mediated immune response that is thought to underlie the development of severe hepatocellular injury. Finally, we describe the clinical management of liver injury in paediatric patients, recognising the scarce evidence to inform decisions about immunosuppression, and consider strategies to help address this risk.