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

TL;DR

A gene therapy using AAV in mice with GSD IX γ2 successfully reduced liver disease and hypoglycemia, showing promise for treating this rare metabolic disorder.

Contribution

Demonstrates that liver-directed AAV gene therapy can correct GSD IX γ2 in mice, with long-term efficacy and fibrosis reduction.

Findings

AAV gene therapy reduced disease burden across all primary endpoints in GSD IX γ2 mice.

The therapy persisted across the mouse lifespan and reduced existing liver fibrosis.

Treatment was effective when administered at different ages and durations.

Abstract

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.

AAV gene therapy shows preclinical promise as a definitive treatment for patients with GSD IX γ2.

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