Liver-Directed Gene Therapy Mitigates Early Nephropathy in Murine Glycogen Storage Disease Type Ia.

Nephropathy is a complication of glycogen storage disease type Ia (GSD-Ia), a metabolic disorder caused by pathogenic variants in glucose-6-phosphatase-α (G6Pase-α or G6PC1). While maintaining blood glucose homeostasis can delay the progression of renal disease in GSD-Ia, the benefits of liver-directed G6PC1 gene therapy on nephropathy remain unclear. This study evaluates the effects of low- and high-dose G6PC1 liver gene augmentation therapy on kidney function. The G6pc-/- mice, which lack G6Pase-α activity in both liver and kidney, were treated with G6PC1 gene therapy to restore either low or near-normal levels of liver G6Pase-α activity, and renal phenotype was examined at age 12 weeks. Both groups exhibited impaired renal glucose homeostasis, altered renal glucose reabsorption, acute kidney injury, and early signs of renal fibrosis. However, mice with near-normal liver G6Pase-α activity had better renal glucose reabsorption and homeostasis with lower serum levels of cystatin C and blood urea nitrogen, key markers of kidney function. These findings highlight the potential of liver-directed G6PC1 gene therapy to enhance metabolic control and mitigate early kidney disease in GSD-Ia.