Glycogen storage disease type Ia (GSD Ia) is a rare inherited disease caused by mutations in the
glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). Absence of G6Pase causes life-threatening
hypoglycemia and long-term complications because of the accumulations of metabolic intermediates.
Bezafibrate, a pan-
peroxisome proliferator-activated receptor (
PPAR) agonist, was administered in the context of genome editing with a
zinc-finger nuclease-containing vector (AAV-ZFN) and a G6Pase donor vector (AAV-RoG6P).
Bezafibrate treatment increased survival and decreased liver size (liver/body mass, p < 0.05) in combination with genome editing.
Blood glucose has higher (p < 0.05) after 4 h of fasting, and
liver glycogen accumulation (p < 0.05) was lower in association with higher G6Pase activity (p < 0.05). Furthermore,
bezafibrate-treated mice had increased numbers of G6PC transgenes (p < 0.05) and higher ZFN activity (p < 0.01) in the liver compared with controls.
PPAR-α expression was increased and
PPAR-γ expression was decreased in
bezafibrate-treated mice. Therefore,
bezafibrate improved hepatocellular abnormalities and increased the transduction efficiency of AAV vector-mediated genome editing in liver, whereas higher expression of G6Pase corrected molecular signaling in GSD Ia. Taken together,
bezafibrate shows promise as a
drug for increasing AAV vector-mediated genome editing.