What is Glycogen Storage Disease (Type I, II)?
 

Glycogen Storage Disease (GSD) is a rare autosomal recessive inherited metabolic disorder caused by defects in enzymes involved in glycogen synthesis or degradation, leading to abnormal glycogen accumulation in organs such as the liver and muscles. At least 19 subtypes are known, with Type I (GSD Type I, hepatic form) and Type II (GSD Type II, Pompe disease) being the most common, accounting for approximately 40% of GSD cases combined. The incidence of GSD I is about 1 in 100,000 to 1 in 20,000, and GSD II is about 1 in 100,000 to 1 in 14,000, with slight variations among subtypes.

GSD I is divided into two subtypes:
 

1.  Ia Type (80% of GSD I): Deficiency of glucose-6-phosphatase (G6PC), leading to the classic GSD Ia tetrad: hypoglycemia, hepatomegaly, hyperlactatemia, hyperuricemia, and hypertriglyceridemia.

2.  Ib Type (20% of GSD I): Deficiency of the G6P transporter (SLC37A4), presenting with the same metabolic abnormalities as Ia plus neutropenia and recurrent infections.

GSD II (Pompe Disease): Accounts for 15% of GSD. Deficiency of lysosomal acid alpha-glucosidase (GAA) leads to glycogen deposition in muscles throughout the body. The infantile form presents with hypertrophic cardiomyopathy and respiratory failure, while the late-onset form presents with progressive muscle weakness. It is classified based on age of onset and primary organs affected into Infantile-Onset Pompe Disease (IOPD) and Late-Onset Pompe Disease (LOPD).
 

(Image: Cleveland Clinic)

Pathogenesis
 

GSD Ia Type: Mutations in the G6PC gene cause glucose-6-phosphatase-α deficiency, preventing hydrolysis of glucose-6-phosphate (G6P) into free glucose within the endoplasmic reticulum lumen. This interrupts glycogenolysis and gluconeogenesis, leading to G6P accumulation in hepatocytes, enhanced glycolysis and lactic acidosis, activation of the pentose phosphate pathway and increased uric acid production, and increased acetyl-CoA leading to hyperlipidemia—forming the classic GSD Ia tetrad. The most common mutations in China are c.648G>T (57%) and c.248G>A (14%).
 

GSD Ib Type: Mutations in the SLC37A4 gene cause deficiency of the glucose-6-phosphate transporter (G6pt), preventing G6P transport from the cytosol into the ER lumen for hydrolysis by G6Pase, resulting in metabolic abnormalities identical to Ia. Additionally, loss of endoplasmic reticulum antioxidant protection in granulocytes leads to increased neutrophil apoptosis and dysfunction. The most common mutations in China are c.572C>T and c.446G>A.

(Image: PubMed)

GSD II Type (Pompe Disease): The causative GAA gene is located at 17q25.3 and contains 20 exons. Mutations reduce lysosomal acid alpha-glucosidase activity, preventing glycogen degradation within lysosomes. This leads to massive accumulation ("glycogen foam") within lysosomes of skeletal, cardiac, and smooth muscle cells, causing vacuolar degeneration, autophagy-mitochondrial dysfunction, and ultimately cell destruction.
 

 

(Image: PubMed)

Gene Therapy
 

Recombinant Adeno-Associated Virus (rAAV) Vectors: For GSD-Ia, DTX401 therapy developed by Ultragenyx involves a single intravenous dose of AAV8-hG6PC (DTX401) to efficiently deliver G6PC cDNA to hepatocytes for sustained expression under a native promoter, restoring G6Pase-α activity and hepatic glucose output. Phase III trials confirmed reduced daytime cornstarch requirements and improved metabolic parameters.

Somatic Cell Gene Therapy: For GSD Ib, uses recombinant adeno-associated virus (rAAV) as a vector to target and deliver the gene sequence encoding human G6PT protein into hepatocyte nuclei. The exogenous gene exists episomally without integrating into the host genome, preserving the cell's original genetic material and offering high safety.

AAV-Mediated Gene Delivery: For GSD-II, systemic AAV9- or AAV8-mediated GAA gene delivery (using muscle- or liver-specific dual promoters) enables sustained secretion of acid alpha-glucosidase by the heart, skeletal muscle, and CNS, clearing lysosomal glycogen. Both infantile and late-onset forms have entered Phase I/II clinical trials.
 

Mouse Models
 

(I) GSD Ia Type

1.  G6pc−/− Mice: High pre-weaning mortality; massive hepatic/renal glycogen and lipid deposition; significantly elevated lactate.

2.  Alb Cre G6pc flox/flox Mice: Spontaneously develop hepatic adenomas/carcinomas, used for long-term toxicity and tumor mechanism studies. Liver-specific G6Pase-α deletion results in milder fasting hypoglycemia (no need for continuous glucose supplementation) and mostly normal renal metabolic parameters.

3.  G6pc-R83C Point Mutation Mice: Model a common human pathogenic mutation; exhibit impaired blood glucose homeostasis and lack hepatic G6Pase-α activity.

(II) GSD Ib Type

1.  G6pt −/− Mice: Show hypoglycemia, hyperlactatemia, and hyperlipidemia similar to Ia, plus neutropenia, intestinal inflammation, and earlier, more severe renal fibrosis.

2.  SLC37A4 Mutant Mice: Exhibit impaired glycogen metabolism.

(III) GSD II Type

1.  GAA −/− Mice: Exhibit systemic GAA enzyme deficiency, lysosomal glycogen accumulation in cardiac and skeletal muscle, left ventricular hypertrophy, and diaphragmatic weakness.

2.  GAA/GYS1 Double Knockout Mice: Elimination of muscle glycogen synthesis significantly reduces glycogen accumulation and cardiac hypertrophy.

3.  GAA p.R484Q Mice: Develop progressive muscle weakness and declining respiratory function from 6 months of age, modeling human late-onset Pompe disease, suitable for long-term efficacy observation.
 

MingCeler Biotech Facilitates Gene Therapy

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various GSD (Type I, II) mouse models according to client needs, such as G6pc−/− mice, Alb Cre G6pc flox/flox mice, G6pc-R83C point mutation mice, G6pt −/− mice, SLC37A4 mutant mice, GAA −/− mice, GAA/GYS1 double knockout mice, and GAA p.R484Q mice. We welcome inquiries!

 

References:

[1] Jiang Jingjing, Ma Mingsheng. Research Status and Therapeutic Advances in Glycogen Storage Disease Type Ib. Rare Diseases Research, 2024, 3(4): 522-526. DOI: 10.12376/j.issn.2097-0501.2024.04.016.

[2] Chou JY, Jun HS, Mansfield BC. Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy. Nat Rev Endocrinol. 2010 Dec;6(12):676-88. doi: 10.1038/nrendo.2010.189. PMID: 20975743; PMCID: PMC4178929.

[3] Dan L, Song X, Yu H. A case of glycogen storage disease type Ia with gout as the first manifestation. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2023 Apr 25;52(2):230-236. doi: 10.3724/zdxbyxb-2022-0530. PMID: 37283108; PMCID: PMC10409914.

[4] Raben N, Nagaraju K, Lee E, Kessler P, Byrne B, Lee L, LaMarca M, King C, Ward J, Sauer B, Plotz P. Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J Biol Chem. 1998 Jul 24;273(30):19086-92. doi: 10.1074/jbc.273.30.19086. PMID: 9668092.

[5] Weinstein DA, Derks TG, Rodriguez-Buritica DF, Ahmad A, Couce ML, Mitchell JJ, Riba-Wolman R, Mount M, Sallago JB, Ross KM, van der Klauw MM, de Boer F, van der Schaaf C, Saavedra H, Martínez-Olmos M, Atanga E, Hosseini A, Mitragotri D, Crombez E. Safety and Efficacy of DTX401, an AAV8-Mediated Liver-Directed Gene Therapy, in Adults With Glycogen Storage Disease Type Ia (GSDIa). J Inherit Metab Dis. 2025 Mar;48(2):e70014. doi: 10.1002/jimd.70014. PMID: 40064185; PMCID: PMC11893205.

[6] Xie Y, Hu B, Gao Y, Tang Y, Chen G, Shen J, Jiang Z, Jiang H, Han J, Yan J, Jin L. Yap signalling regulates ductular reactions in mice with CRISPR/Cas9-induced glycogen storage disease type Ia. Anim Cells Syst (Seoul). 2022 Nov 7;26(6):300-309. doi: 10.1080/19768354.2022.2139755. PMID: 36605584; PMCID: PMC9809376.

[7] Arnaoutova I, Aratyn-Schaus Y, Zhang L, Packer MS, Chen HD, Lee C, Gautam S, Gregoire FM, Leboeuf D, Boule S, Fernandez TP, Huang V, Cheng LI, Lung G, Bannister B, Decker J, Leete T, Shuang LS, Bock C, Kothiyal P, Grayson P, Mok KW, Quinn JJ, Young L, Barrera L, Ciaramella G, Mansfield BC, Chou JY. Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia. Nat Commun. 2024 Nov 10;15(1):9729. doi: 10.1038/s41467-024-54108-1. PMID: 39523369; PMCID: PMC11551175.

Special Statement: This article is from the MingCeler Biotech WeChat public account. Personal forwarding to Moments is welcome. Media or institutions are prohibited from reprinting to other platforms without authorization. For reprint authorization, please contact us via the public account backend. For other cooperation needs, please contact sales@mingceler.com.

Disclaimer: Some materials are sourced from the internet. If there is any infringement, please contact us for removal. This article is intended for informational purposes only and does not provide treatment recommendations. The views expressed herein do not represent the position of MingCeler Biotech, nor does MingCeler Biotech support or oppose the views expressed.