Hepatic lentiviral gene transfer prevents the long-term onset of hepatic tumours of glycogen storage disease type 1a in mice

International audienceGlycogen storage disease type 1a (GSD1a) is a rare disease due to the deficiency in theglucose-6-phosphatase catalytic subunit (encoded by G6pc), which is essential forendogenous glucose production. Despite strict diet control to maintain blood glucose, patientswith GSD1a develop hepatomegaly, steatosis and then hepatocellular adenomas (HCA),which can undergo malignant transformation. Recently, gene therapy has attracted attention asa potential treatment for GSD1a. In order to maintain long-term transgene expression, wedeveloped an HIV-based vector, which allowed us to specifically express the human G6PCcDNA in the liver. We analysed the efficiency of this lentiviral vector in the prevention of thedevelopment of the hepatic disease in an original GSD1a mouse model, which exhibitsG6Pase deficiency exclusively in the liver (L-G6pc-/- mice). Recombinant lentivirus wereinjected in B6.G6pcex3lox/ex3lox.SAcreERT2/w neonates and G6pc deletion was induced bytamoxifen treatment at weaning. Magnetic resonance imaging was then performed to followup the development of hepatic tumours. Lentiviral gene therapy restored glucose-6phosphatase activity sufficient to correct fasting hypoglycaemia during 9 months. Moreover,lentivirus-treated L-G6pc-/- mice presented normal hepatic triglyceride levels, whereasuntreated mice developed steatosis. Glycogen stores were also decreased although liverweight remained high. Interestingly, lentivirus-treated L-G6pc-/- mice were protected againstthe development of hepatic tumours after 9 months of gene therapy while most of untreated LG6pc-/-mice developed millimetric HCA. Thus the treatment of new-borns by recombinantlentivirus appears as an attractive approach to protect the liver from the development ofsteatosis and hepatic tumours associated to GSD1a pathology