Gene therapy in pediatric liver disease

The liver is an attractive organ for the development of gene-based therapeutic approaches. In the recent years, gene therapy for monogenic diseases of the liver using recombinant adeno-associated virus (rAAV) has shown safety and in some cases efficacy in clinical trials in adult subjects with hemophilia A and B and acute intermittent porphyria. Multi-year expression of the transgenes has been documented, making liver gene therapy a promising curative treatment. The success is consequent to more than two decades of experimentation in small- and large-animal models and humans. This work allowed investigators to understand and overcome some of the major immunological hurdles, such as humoral and cellular responses to the vector. However, due to the loss of viral DNA during hepatocyte proliferation, AAV vector-mediated liver gene transfer is predicted to be less durable in neonatal and pediatric subjects. Modulation of the antibody response against the viral capsid is being explored to allow for readministration of the vector. Alternatively, the permanent modification of the hepatocyte genome in vivo could overcome this limitation. This chapter focuses on different gene therapy approaches that can be applied to cure monogenic liver diseases. The basic concepts of gene replacement therapy are presented. Key experiments in animal models, as well as innovative approaches based in the use of engineered endonucleases to modify permanently the hepatocyte genome are discussed.