Liver-directed AAV gene therapy in mice corrects glycogen storage disease type IX γ2.

Glycogen storage disease (GSD) type IX γ2 is a rare inborn error of metabolism where a defect in glycogenolysis leads to the inability to break down glycogen in the liver. Patients with GSD IX γ2 develop hypoglycemia and advanced liver disease, placing them at risk for liver transplantation. This study evaluates the efficacy of liver-directed AAV gene therapy in a murine model of GSD IX γ2. Phkg2-/- mice underwent treatment with AAV gene therapy (AAV9-LSP-mPhkg2, 5 × 1012 vg/kg, intravenous delivery) at ages 3 or 6 months and were treated for either 2 weeks, 3 months, or 12 months. Results demonstrated that AAV gene therapy reduced GSD IX γ2 disease burden across all primary end points. AAV gene therapy also persisted across the mouse lifespan and reduced preexisting liver fibrosis. This work provides preclinical data supporting AAV gene therapy as a definitive treatment for GSD IX γ2.