Treatment of genetic liver disease by locus-specific genome editing in vivo

Precise gene repair involves the correction of the disease-causing mutation directly at the defective locus. This strategy has an immense therapeutic potential for the treatment of genetic liver disease when combined with very powerful delivery systems for gene transfer such as recombinant adeno-associated viral vectors (rAAVs). The aim of this project was to deliver CRISPR/Cas9-mediated gene repair reagents using highly hepatotropic rAAVs for correction of the OTC gene in patient hepatocytes. In order to do so, editing reagents were first evaluated in a murine model containing a transposed version of the human OTC gene. Once the reagents were validated, these were delivered to the chimeric livers of humanized mice engrafted with OTC patient-derived primary human hepatocytes. In this study we demonstrated precise in vivo molecular repair of the disease-causing mutation.