Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia

Abstract Glycogen storage disease type-Ia (GSD-Ia) patients, deficient in glucose-6-phosphatase-α (G6Pase-α or G6PC), manifest impaired glucose homeostasis with hallmark fasting hypoglycemia. We generated a humanized knock-in mouse model, huR83C, that is homozygous for the pathogenic G6PC-R83C variant and manifests a GSD-Ia phenotype. We evaluated the efficacy of BEAM-301, lipid nanoparticles containing guide RNA and mRNA encoding a newly-engineered adenine base editor, to correct the G6PC-R83C variant in huR83C mice and monitored phenotypic correction through one year. BEAM-301-treated mice exhibited a maximum base-editing efficiency of ~60% in the liver and achieved physiologicallevels of hepatic G6Pase-α activity with just ~10% base-editing rate. The edited mice displayed an improved metabolic phenotype, sustained 24-hour fasting, and survived long-term. In contrast, untreated mice exhibited fasting hypoglycemia and died prematurely. The durable pharmacological efficacy of base editing in huR83C mice supports the development of BEAM-301 as a potential therapeutic for patients with GSD-Ia carrying the G6PC-R83C variant.