Lee Cheol, Pratap Kunal, Zhang Lisa, Chen Hung Dar, Arnaoutova Irina, Starost Matthew F, Mansfield Brian C, Chou Janice Y
Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA.
Division of Veterinary Resources, National Institutes of Health, Bethesda, Maryland, USA.
J Inherit Metab Dis. 2025 Jul;48(4):e70048. doi: 10.1002/jimd.70048.
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.
肾病是Ia型糖原贮积病（GSD-Ia）的一种并发症，GSD-Ia是一种由葡萄糖-6-磷酸酶-α（G6Pase-α或G6PC1）的致病变体引起的代谢紊乱疾病。虽然维持血糖稳态可以延缓GSD-Ia患者肾脏疾病的进展，但肝脏靶向G6PC1基因治疗对肾病的益处仍不明确。本研究评估了低剂量和高剂量G6PC1肝脏基因增强治疗对肾功能的影响。在肝脏和肾脏中均缺乏G6Pase-α活性的G6pc-/-小鼠接受了G6PC1基因治疗，以恢复肝脏G6Pase-α活性的低水平或接近正常水平，并在12周龄时检查肾脏表型。两组均表现出肾脏葡萄糖稳态受损、肾脏葡萄糖重吸收改变、急性肾损伤以及肾纤维化的早期迹象。然而，肝脏G6Pase-α活性接近正常的小鼠具有更好的肾脏葡萄糖重吸收和稳态，血清胱抑素C和血尿素氮水平较低，这两种物质是肾功能的关键标志物。这些发现突出了肝脏靶向G6PC1基因治疗在增强GSD-Ia患者代谢控制和减轻早期肾脏疾病方面的潜力。
