AAV-Mediated Gene Transfer to the Liver

: The liver is a frequent target of gene-transfer experiments, because of its central role in many metabolic and synthetic pathways. For applications where prolonged expression of genes in the liver is required, adeno-associated virus (AAV) has proven to be an effective tool for in vivo gene transfer. High-level, persistent hepatic expression has been achieved in a number of experimental systems following a single treatment with AAV in murine and larger animal models. This prolonged expression is particularly useful for the treatment of genetic diseases such as the inborn errors of metabolism, where lifelong expression of the deficient enzyme may be required. Therapeutic benefits using AAV vectors have been demonstrated in animal models of amino acid disorders, lysosomal storage diseases, and coagulopathies (3-5), and Phase I clinical trials are proposed for the treatment of hemophilia B (6). Gene transfer to the murine liver using AAV is achieved by intravenous (iv) injection of recombinant virus, either via a peripheral or portal vein. The liver is the primary organ transduced following intravenous injection of AAV, although other tissues such as heart and lung may also take up virus to a lesser extent when peripheral injection sites are used (7). Portal-vein injection can reduce the amount of extra-hepatic transduction, and allows a larger dose of virus to be delivered to the liver. However, this technique requires surgical expertise, and can only be performed on adult mice.