AAV-Mediated Gene Delivery to the Mouse Liver.

The liver is an attractive target for gene therapy due to the high incidence of liver disease phenotypes. Adeno-associated viral vectors (AAV) are currently the most popular gene delivery system for targeting the liver, reflecting high transduction efficiency in vivo and the availability of a toolkit of multiple different capsids with high liver tropism. While AAV vectors confer stable gene transfer in the relatively quiescent adult liver, the predominantly episomal nature of AAV vector genomes results in less stable expression in the growing liver as a consequence of episome clearance during hepatocellular replication. This is an important consideration in experimental design involving young animals, particularly mice, where liver growth is rapid. Given the immense value of murine models for dissecting disease pathophysiology, experimental therapeutics and vector development, this technical manuscript focuses on AAV-mediated transduction of the mouse liver. Xenograft models, in which chimeric mouse-human livers can be established, are also amenable to AAV-mediated gene transfer and have proven to be powerful tools for in vivo selection and characterization of novel human-specific capsids. While yet to be confirmed, such models have the potential to more accurately predict transduction efficiency of clinical candidate vectors than nonhuman primate models.