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

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Cheol Lee, Kunal Pratap, Lisa Zhang, Hung Dar Chen, Irina Arnaoutova, Matthew F. Starost, Brian C. Mansfield, Janice Y. Chou
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Abstract

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.

肝导向基因治疗减轻小鼠Ia型糖原储存病的早期肾病
肾病是Ia型糖原储存病(GSD-Ia)的并发症,是一种由葡萄糖-6-磷酸酶-α (G6Pase-α或G6PC1)致病性变异引起的代谢紊乱。虽然维持血糖稳态可以延缓GSD-Ia肾病的进展,但肝脏导向的G6PC1基因治疗对肾病的益处尚不清楚。本研究评估低剂量和高剂量G6PC1肝基因增强治疗对肾功能的影响。在G6PC1基因治疗下,肝脏和肾脏均缺乏G6Pase-α活性的G6pc - / -小鼠恢复了低水平或接近正常水平的肝脏G6Pase-α活性,并在12周龄时检查肾脏表型。两组均表现出肾葡萄糖稳态受损、肾葡萄糖重吸收改变、急性肾损伤和肾纤维化的早期症状。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,这是肾功能的关键指标。这些发现强调了肝脏导向的G6PC1基因治疗在GSD-Ia中增强代谢控制和减轻早期肾脏疾病的潜力。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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