In vertebrates, the liver is the central metabolic organ of the body, which carries out an estimated 500 functions that range from general detoxification to protein synthesis, bile production, metabolism of fats, carbohydrates, proteins, bilirubin, vitamin and mineral storage and it even has an immune function. Hepatocytes are considered the professional liver cells, which carry out all these functions. With such a variety of tasks to perform, it is not surprising that more than 400 rare monogenic disorders of hepatic origin have been described. For many of these, liver transplantation remains the only curative strategy, however, this is limited by organ availability and requires lifelong immune suppression. The fact that liver transplantation is curative led to the assumption that the restoration of the expression of the defective gene would result in the resolution of the disease. Thus, liver-directed gene therapy and gene editing strategies have emerged as promising alternatives to transplantation in inherited monogenic liver disorders. To date, the most efficient vectors for delivering genetic material to the nucleus of liver cells and leading to long term expression of the therapeutic transgene are based on adeno-associated viral vectors (AAVs).

Herein, we will present our more recent progresses on the development of AAV-mediated gene addition and AAV-CRISPR-Cas9 gene editing approaches for the treatment of Wilson’s disease and Primary hyperoxaluria type I, respectively.