Glycogen Storage Disease (GSD) Animal Model Service
Glycogen storage disease (GSD) encompasses a group of inherited metabolic disorders caused by deficiencies in enzymes involved in glycogen synthesis or degradation, leading to abnormal glycogen accumulation in tissues such as liver, muscle, and heart. Protheragen provides fully customizable GSD animal models tailored to specific GSD subtypes (type I, II, III, IV, V, VI, VII, etc.). From precise genetic engineering to phenotypic characterization and pharmacological intervention studies, we deliver reliable, clinically relevant models to accelerate your drug discovery and preclinical research programs.
Overview of Glycogen Storage Disease (GSD) Animal Models
GSD animal models are indispensable tools for elucidating disease pathophysiology, evaluating therapeutic candidates, and advancing gene- or enzyme-based therapies. Each GSD subtype results from a distinct enzymatic defect, for instance, glucose-6-phosphatase deficiency in GSD I, acid alpha-glucosidase deficiency in GSD II (Pompe disease), and glycogen phosphorylase deficiency in GSD V (McArdle disease). Rodent models (primarily mice and rats) recapitulate key human disease features, including hypoglycemia, hepatomegaly, cardiomyopathy, exercise intolerance, and progressive muscle weakness. These models enable quantitative assessment of glycogen accumulation, tissue pathology, metabolic disturbances, and response to investigational drugs, thereby bridging the gap between in vitro findings and clinical translation.
Fig.1 Early Gys1 ASO treatment in Gaa-/- mice reduces target mRNA and protein, lowering skeletal muscle glycogen. (Weiss, L., et al., 2025)
Our Services
Leveraging our extensive expertise in metabolic disease modeling, proprietary gene modification platforms, and rigorous preclinical pharmacology capabilities, Protheragen offers a comprehensive suite of GSD animal model services. These include de novo model generation (knockout, knock-in, and conditional alleles), colony maintenance, deep phenotyping (histology, biochemical assays, and imaging), as well as efficacy testing of small molecules, oligonucleotides, and gene therapies.
Animal Models of Glycogen Storage Disease (GSD)
Custom development of GSD animal models is available to meet specific research needs across different subtypes and genetic backgrounds. Leveraging established gene-modification platforms, models are generated on demand, from targeted gene knockout or knock-in designs to conditional alleles, followed by full phenotypic validation. Each model and research project are custom-built to recapitulate the desired enzymatic defect, tissue glycogen accumulation pattern, and clinically relevant biomarkers, ensuring alignment with specific drug discovery or translational objectives.
Genetically engineered models represent the predominant and most physiologically relevant approach for GSD, enabling precise recapitulation of human enzyme deficiencies. Custom development includes global or tissue-specific knockouts, point mutation knock-ins, and humanized alleles. Developmental timelines, mutation types, and strain backgrounds are tailored to each program.
- G6pc knockout model
- Agl knockout model
- Pygm knockout model
- Gaa knockout model
- Gbe1 knockout model
- Pygl knockout model
- Pfkm knockout model
- Other models
Mouse Model for Glycogen Storage Disease (GSD) Research
| Model Name | Modeling Method | Detailed Description |
|---|---|---|
| Galns-Flox Mouse Model | Conditional Knockout | In this strain, loxP sites are positioned around exons 2 through 4 of the GALNS gene. Following breeding with a strain that expresses Cre recombinase, the strain enables conditional, tissue-specific disruption of GALNS expression. |
| Galns-KO Mouse Model | Knockout | Deletion of exons 2 to 4 from the Galns gene produces a Galns knockout mouse. |
| G6pc-Flox Mouse Model | Conditional Knockout | Flanking loxP sites are introduced on either side of G6pc exon 3. Upon crossing with a Cre recombinase-expressing line, this model allows conditional elimination of G6pc expression in a tissue-specific manner. |
| G6pc-KO Mouse Model | Knockout | Removal of G6pc exon 3 yields G6pc knockout mice. |
| Gaa-KO Mouse Model | Knockout | Gene-editing methods are used to eliminate the segment covering exons 3 through 15 in this strain. |
| Gbe1-KO Mouse Model | Knockout | Targeted deletion of Gbe1 exon 2 generates Gbe1 knockout mice. |
| Hif1a-Flox Mouse Model | Conditional Knockout | LoxP sites are placed around Hif1a exon 2 in this strain. Mating with a Cre recombinase-expressing strain facilitates tissue-specific conditional knockout of Hif1a expression. |
| Pfkm-KO Mouse Model | Knockout | Knockout of the Pfkm gene is achieved by deleting exon 3, resulting in Pfkm-deficient mice. |
| B6-PRKAG2 Mouse Model | Knock-in | Knock-in mutation in the Prkag2 gene mimics human cardiac congenital glycogen storage disease. |
| Prkag2-KO Mouse Model | Knockout | Global knockout of Prkag2 results in AMPK γ2 deficiency and altered glycogen metabolism. |
| … | … | … |
Case Study-Gaa-KO Mouse Model Development
Model Introduction
A Gaa-knockout mouse model was developed to recapitulate human Pompe disease (Glycogen Storage Disease Type II), an autosomal recessive lysosomal storage disorder caused by a deficiency of acid alpha-glucosidase (GAA). The primary objective was to generate a knockout strain featuring targeted disruption of the Gaa gene spanning exons 3 through 15, thereby ensuring loss of functional GAA enzyme. This model provides a reliable platform for investigating disease progression from early metabolic changes to late-stage pathology, as well as for evaluating the efficacy of various therapeutic interventions, including enzyme replacement and gene therapy.
Methodology
- Animal Model: The mouse Gaa gene comprises 20 exons, with the start codon located in exon 2 and the stop codon in exon 20. Using gene-editing technology, the genomic region spanning exons 3 to 15 was selectively deleted. This strategy eliminated the majority of the coding sequence, preventing translation of functional GAA protein. Homozygous knockout (Gaa-KO) mice were generated on a C57BL/6 background, and wild-type (WT) littermates were used as controls. All animals were housed under specific pathogen-free conditions with standard chow and water ad libitum.
- Phenotypic Analysis Methods: Body weight and grip strength were measured in 12-week-old homozygous female mice to assess general metabolic and neuromuscular status. Tissue glycogen content was quantified in the heart and gastrocnemius muscle using enzymatic assays. GAA enzyme activity in the same tissues was measured fluorometrically with a specific substrate. All assays were compared between Gaa-KO and WT groups.
Phenotypic Analysis & Results
At 12 weeks of age, homozygous female Gaa-KO mice demonstrated notably reduced grip strength relative to wild-type (WT) controls, a finding indicative of progressive muscle weakness that mirrors the clinical presentation of Pompe disease. This neuromuscular deficit was accompanied by a consistently elevated body weight in the knockout group compared to WT mice, aligning with the well-documented metabolic alterations associated with GAA deficiency.
Fig.2 Grip strength testing and body weight of 12-week-old homozygous female Gaa-KO mice and wild-type (WT) mice. Data are presented as mean ± SEM (n=5; *p < 0.05).
Tissue analysis further revealed marked glycogen deposition in both cardiac and gastrocnemius muscle of Gaa-KO mice when compared to WT controls. The most pronounced increase was detected in heart tissue, whereas a more modest accumulation was seen in skeletal muscle. In direct contrast, GAA enzymatic activity in these same tissues was severely diminished in knockout animals relative to wild-type levels. The reciprocal relationship between elevated glycogen content and reduced enzyme activity confirms the successful recapitulation of the Pompe disease phenotype at the biochemical level.
Fig.3 Glycogen content detection and GAA activity detection in the heart and gastrocnemius muscle of 12-week-old homozygous female Gaa-KO mice and wild-type (WT) mice. Data are presented as mean ± SEM (n=5; ***p < 0.001, *p < 0.05).
Conclusion
The Gaa-KO mouse model generated by deleting exons 3-15 successfully recapitulated the core phenotypic features of Pompe disease, including reduced muscle strength, elevated body weight, pathological glycogen storage in cardiac and skeletal muscles, and severely deficient GAA enzymatic activity. This model is well-suited for preclinical evaluation of enzyme replacement, gene therapy, and small-molecule approaches for GSD II.
Contact Us
Protheragen's GSD animal model services extend beyond basic model generation to full-spectrum preclinical support, including pharmacokinetic studies in GSD models to characterize the absorption, distribution, metabolism, and excretion of novel therapeutic candidates; thorough safety pharmacology and toxicology assessments; efficacy studies with validated endpoints such as tissue glycogen quantification, histomorphometry, serum biomarkers (e.g., glucose, CK, liver enzymes), and functional tests; and study reports with customized data packages to support IND filing. For a detailed discussion on how our GSD models can streamline your drug development pipeline, please contact us.
Reference
- Weiss, Lan et al. "Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease." Clinical and translational medicine 15.4 (2025): e70314.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.