RARE DISEASE
Glycogen storage disease due to glycogen debranching enzyme deficiency
Glycogen storage disease due to glycogen debranching enzyme deficiency
Glycogen storage disease due to glycogen debranching enzyme deficiency
Synonyms: Amylo-1,6-glucosidase deficiency, Cori disease, Cori-Forbes disease, Forbes disease, GDE deficiency, GSD due to glycogen debranching enzyme deficiency, GSD type 3, GSDIII, Glycogen storage disease type 3, Glycogen storage disease type III, Glycogenosis due to glycogen debranching enzyme deficiency, Glycogenosis type 3, Glycogenosis type III, Limit dextrinosis
Synonyms: Amylo-1,6-glucosidase deficiency, Cori disease, Cori-Forbes disease, Forbes disease, GDE deficiency, GSD due to glycogen debranching enzyme deficiency, GSD type 3, GSDIII, Glycogen storage disease type 3, Glycogen storage disease type III, Glycogenosis due to glycogen debranching enzyme deficiency, Glycogenosis type 3, Glycogenosis type III, Limit dextrinosis
Synonyms: Amylo-1,6-glucosidase deficiency, Cori disease, Cori-Forbes disease, Forbes disease, GDE deficiency, GSD due to glycogen debranching enzyme deficiency, GSD type 3, GSDIII, Glycogen storage disease type 3, Glycogen storage disease type III, Glycogenosis due to glycogen debranching enzyme deficiency, Glycogenosis type 3, Glycogenosis type III, Limit dextrinosis
Drug discovery
2
drugs
With orphan designations
Overview
Glycogen Storage Disease Type III (GSD III) is an autosomal recessive disorder caused by AGL gene mutations, leading to glycogen debranching enzyme deficiency. This results in abnormal glycogen accumulation in the liver, skeletal/cardiac muscles, and occasionally other organs. Clinical features include fasting hypoglycemia, hepatomegaly, hyperlipidemia, and progressive myopathy/cardiomyopathy (GSD IIIa). Variability in phenotype correlates with residual enzyme activity, with liver symptoms often improving by adolescence while neuromuscular complications may progress [1][6][18].
Population
Incidence: ~1:100,000 globally, but higher (~1:5,400) in North African Jewish populations due to founder mutations.
Subtypes: IIIa (85% of cases, liver/muscle involvement), IIIb (15%, liver-limited) [6][14][18].
Age of onset: Symptoms (hypoglycemia, hepatomegaly) typically emerge in infancy/early childhood [1][17].
Burden
Pediatric: Growth retardation, recurrent hypoglycemia, and delayed motor milestones [1][5][16].
Adult: Progressive skeletal myopathy, cardiomyopathy, and cirrhosis in ~20% of cases [1][6][15].
Psychosocial impact: Lifelong dietary restrictions, disability from neuromuscular degeneration, and reduced quality of life [12][15][17].
Therapies
Dietary management: Frequent high-protein meals, uncooked cornstarch to prevent hypoglycemia; may improve growth/metabolic parameters [1][5][15].
Experimental approaches: Truncated GDE gene therapy via AAV vectors (preclinical success in restoring muscle/hepatic function) [3][8][13].
Supportive care: Monitoring for cirrhosis, cardiomyopathy, and myopathy progression [17][18].
Categories: rare cardiac diseases, rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
117 drug discovery papers about Glycogen storage disease due to glycogen debranching enzyme deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
117 drug discovery papers about Glycogen storage disease due to glycogen debranching enzyme deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-11 | High-Protein Diet Ameliorates Cardiomyopathy in a Cardiac-Specific AGL Knockout Mouse Model: Association With Upregulated Hepatic Gluconeogenesis.
Glycogen storage disease type IIIa (GSDIIIa) causes progressive cardiomyopathy, and current high-fat dietary strategies lack consensus regarding long-term cardiovascular safety. We evaluated the efficacy and safety of high-protein versus high-fat diets in a novel cardiac-specific AGL knockout (CKO; AGLflox/flox/MHC-Cre) mouse model to specifically assess isolated cardiac responses. CKO mice were randomized at weaning to High-Protein (HPD), High-Protein High-Fat (HPHFD), or Low-Protein (LPD) diets, with approximate protein/fat/carbohydrate distributions of 40%/4%/50%, 40%/50%/10%, and 10%/4%/80%, respectively; CKO mice on normal diet (ND) and AGLflox/flox mice served as controls. Cardiac phenotypes and hepatic gluconeogenic enzymes were evaluated longitudinally up to 24 weeks. CKO-ND mice developed progressive cardiomyopathy with elevated myocardial glycogen at 24 weeks (32.01 ± 3.22 vs. 5.90 ± 2.21 mg/g in controls, p < 0.001), reduced left ventricular ejection fraction, and elevated serum creatine kinase. Both HPD and HPHFD significantly reduced myocardial glycogen burden (12.82 ± 3.58 and 15.07 ± 4.40 mg/g, p < 0.001), restored systolic function, and normalized hypertrophy. However, HPHFD induced distinct hyperlipidemia, whereas HPD maintained a stable lipid profile. Furthermore, therapeutic benefits in high-protein groups were associated with upregulated hepatic rate-limiting gluconeogenic enzymes (FBP2, PCK1). In this cardiac-specific AGL knockout model, a high-protein, non-high-fat diet attenuated cardiac glycogen accumulation and systolic dysfunction without the hyperlipidemia observed with the high-fat regimen. These preclinical findings support further evaluation of high-protein dietary strategies for GSDIIIa cardiomyopathy and suggest a possible liver-heart metabolic axis involving hepatic gluconeogenesis.
2026-04-14 | Effects of Extended-Release Cornstarch Supplementation on Glycemic Stability and Metabolic Parameters in Korean Patients with Glycogen Storage Disease.
Background/Objectives: Patients with hepatic glycogen storage disease (GSD) require frequent nighttime intake of uncooked corn starch (UCCS) to prevent fasting hypoglycemia, which imposes a substantial burden. Glycosade, an extended-release cornstarch, was developed to prolong overnight glucose availability. However, data regarding South Korean patients are limited. Therefore, we aimed to evaluate the efficacy and safety of Glycosade in South Korean patients with hepatic GSD. Methods: In this single-center prospective observational study, patients with hepatic GSD underwent laboratory evaluations before and 1 month after Glycosade administration. Continuous glucose monitoring (CGM) was performed during UCCS and Glycosade administration periods. The nocturnal mean glucose, coefficient of variation, time in range (70-180 mg/dL), and time below the range (<70 and <54 mg/dL) were compared between the periods using paired analyses. Results: No significant differences were observed in the nocturnal CGM metrics between the treatment periods. However, time-aligned CGM profiles revealed distinct temporal patterns, with a decline in glucose levels approximately 3-4 h after UCCS intake, whereas Glycosade showed a more sustained glucose profile over an extended period. Liver enzyme and lipid levels improved significantly after 1 month of Glycosade supplementation. Conclusions: In a cohort of South Korean patients with hepatic GSD, Glycosade maintained nocturnal glycemic stability comparable to that of conventional cornstarch without increasing the risk of hypoglycemia. Glycosade was also associated with improved biochemical parameters, supporting its role in nighttime dietary management.
2026-04-02 | Bone mineral density assessment in pediatric patients with hepatic glycogen storage disease subtypes
Background: current scientific literature regarding bone mineral density (BMD) profiles in children with hepatic glycogen storage diseases (GSD) remains sparse. The underlying mechanisms of bone pathology in these patients are not yet fully elucidated. Primary contributors to BMD reduction in GSD include suboptimal metabolic control, mobilization of bone calcium and phosphates to compensate for metabolic shifts, hepatic dysfunction, muscular impairment, hypogonadism, and various micronutrient deficiencies. Aim: to investigate the correlations between BMD parameters and clinical, laboratory, and instrumental findings in pediatric patients with hepatic GSD subtypes. Materials and Methods: the study involved 72 patients aged 4 to 17 years (median age: 8.9 [6.7; 13.8]) diagnosed with GSD types I, III, VI, and IX. Lumbar spine BMD was evaluated using dual-energy X-ray absorptiometry (DXA). Multivariate linear regression was utilized to analyze the associations between variables. Results: the mean BMD Z-score for the entire cohort was within the physiological range (-0.13±1.3). However, 4% (n=3) of patients demonstrated reduced BMD relative to chronological age. A history of at least one fracture was noted in 19% (n=14) of cases, with 5% (n=4) resulting from low-energy trauma. The BMD Z-score showed a significant negative correlation with age (p=0.002) and serum levels of ALT (p=0.031), AST (p=0.028), and alkaline phosphatase (p=0.009). Conversely, positive associations were identified with height Z-score (p<0.001), acid-base status (p=0.02), HDL-cholesterol (p=0.034), glucose levels (p=0.088), and the presence of hepatic fibrosis (p=0.049). Increased fracture incidence was significantly associated with female sex (p=0.039) and liver fibrosis (p=0.02). Conclusion: advanced age, growth retardation (low height Z-score), metabolic disturbances (acidosis, hypoglycemia, dyslipidemia), hepatic cytolysis, and the presence of liver fibrosis represent significant risk factors for BMD reduction in pediatric hepatic GSD KEYWORDS: glycogen storage disease, pediatric patients, bone mineral density, osteoporosis, fractures, liver. FOR CITATION: Rakhmanina K.Yu., Tin I.F., Pavlovskaya E.V., Taran N.N., Bagaeva M.E., Abdulmanapova M.A., Zubovich A.I., Strokova T.V. Bone mineral density assessment in pediatric patients with hepatic glycogen storage disease subtypes. Russian Journal of Woman and Child Health. 2026;9(1):50–60 (in Russ.). DOI: 10.32364/2618-8430-2026-9-1-7
2026-03-09 | Hepatic Glycogen Storage Diseases in Brazil: A Multicenter Study.
To describe clinical and laboratory characteristics, emphasizing the evolution of patients with hepatic glycogen storage diseases (GSDs) followed in Brazilian reference centers. Multicenter, retrospective study involving 13 centers, using RedCap platform. 132 patients were included: 63 (47.8%) GSD type I (56 Ia, 7 Ib), 13 (9.8%) with type III (12 IIIa, 1 IIIb), 1 (0.8%) type IV, 6 (4.5%) type VI, and 49 (37.1%) with type IX (28 IXa, 7 IXb, and 14 IXc). Type I patients presented earlier (4 months) and had more episodes of hypoglycemia at clinical presentation (p < 0.001). Anthropometric data at admission revealed impaired growth, with a tendency toward short stature across the groups (median -2.06, -1.89, and -1.96 among type I, III, and IX respectively). The median body mass index (BMI) z-scores at admission for all three types were above +1. Only patients with type IX demonstrated significant improvement in height (p = 0.007) and BMI (p = 0.020) z-scores during follow-up. Regarding laboratory tests, significant decreases were observed in total cholesterol, triglycerides, venous lactate and aminotransferases in patients with types I and IX. Hepatic GSDs are heterogeneous diseases. There is a significant height impairment with a troublesome trend to overweight and obesity, especially in type I. Although there is improvement in aminotransferases, cholesterol, and triglycerides with follow-up, adherence to treatment remains a challenge.
2026-02-09 | Enhanced lysosomal glycogen breakdown is associated with liver tumorigenesis in glycogen storage disease type III.
Glycogen storage disease type III (GSDIII) is a rare metabolic disorder caused by mutations in the glycogen debranching enzyme (AGL), leading to hepatic glycogen accumulation, fibrosis and increased hepatocellular carcinoma (HCC) risk. This study investigates the metabolic mechanisms driving liver tumorigenesis in an Agl -/- model of GSDIII. Liver and tumor samples from 14-month-old Agl -/- and Agl +/+ mice, and liver biopsies from patients with GSDIII (n = 4), were analyzed using histological, biochemical and molecular approaches. Agl -/- mice recapitulated key features of GSDIII, including a 3.5-fold hepatic glycogen overload (p <0.001), and chronic liver disease. More than 30% of the animals developed liver tumors, associated with a 2.5-fold increase in alpha-fetoprotein levels (p <0.005). Despite marked reductions in glucose (7.5-fold, p <0.0001), glucose-6 phosphate (266-fold, p <0.0001), lactate (8-fold, p <0.005), cholesterol (1.9-fold, p <0.001) and triglyceride levels (6.2-fold, p <0.001) in the liver, glycaemia was maintained at around 87.0 ± 9.6 mg/dl after 6 h of fasting, through activated extrahepatic, but not hepatic, gluconeogenesis. Intriguingly, most tumors exhibited lower glycogen content than surrounding tissue (3.3-fold decrease, p <0.0001), which was associated with increased lysosomal alpha-acid glucosidase activity (19.5 ± 5.5 in tumor vs. 9.9 ± 2.0 mmol/h/mg in Agl -/- liver; p <0.0005) and the presence of glycophagosomes. PAS-negative staining in HCCs from patients with GSDIII supported these observations. Although YAP nuclear staining varied among tumors, the overall increase in YAP nuclear localization and CTGF expression suggests that inhibition of the Hippo/YAP pathway may contribute to tumorigenesis in GSDIII hepatocytes. In GSDIII, liver metabolism is characterized by the accumulation of structurally abnormal glycogen and a significant reduction of key energy substrates. In this metabolic context, enhanced lysosomal glycogen degradation may support tumor growth, highlighting a mechanistic link between glycogen metabolism and the development of liver cancer. This study provides novel insights into the metabolic dysregulations driving liver tumorigenesis in glycogen storage disease type III (GSDIII). Our findings reveal a potential link between abnormal glycogen accumulation and liver cancer, highlighting the pivotal role of lysosomal glycogen degradation in supporting tumor growth. These results are particularly important for researchers and clinicians working on metabolic liver diseases, as they suggest potential glycogen-targeting therapeutic strategies for GSDIII and other related liver disorders. Practically, they could guide future interventions aimed at modulating glycogen metabolism, offering new treatment avenues for patients with GSDIII at risk of hepatocellular carcinoma, while contributing to the broader understanding of metabolic dysregulation in cancer biology.
proteins
2025-07-02 | Molecular architecture and catalytic mechanism of human glycogen debranching enzyme.
Glycogen, a key branched glucose polymer, acts as a vital energy reservoir in mammalian cells, particularly during intense activity or fasting. The glycogen debranching enzyme (GDE) plays a key role in glycogen degradation by removing branches, ensuring efficient glucose release. Dysfunction of GDE leads to the accumulation of limit dextrin and is implicated in the pathogenesis of Glycogen Storage Disease Type III (GSD III). We present the cryo-EM structure of human GDE (hsGDE) at 3.23 Å resolution, providing molecular insights into its substrate selectivity and catalytic mechanism. Our study further investigates the molecular consequences of disease-associated mutations by correlating structural data with enzymatic activities of representative GSD III-causing variants. We discover that these mutations induce GSD III through diverse mechanisms, including significant reductions in enzymatic activity, and disruptions to the glycogen-bound region and overall structural integrity. The elucidation of these pathways not only advances our understanding of hsGDE's role in substrate recognition and catalysis but also illuminates the molecular pathology of GSD III. Our findings pave the way for the development of targeted therapeutic strategies for this disease.
2024-07-18 | A Functional Human Glycogen Debranching Enzyme Encoded by a Synthetic Gene: Its Implications for Glycogen Storage Disease Type III Management.
Glycogen Storage Disease type III (GSD III) is a metabolic disorder resulting from a deficiency of the Glycogen Debranching Enzyme (GDE), a large monomeric protein (approximately 170 kDa) with cytoplasmic localization and two distinct enzymatic activities: 4-α-glucantransferase and amylo-α-1,6-glucosidase. Mutations in the Agl gene, with consequent deficiency in GDE, lead to the accumulation of abnormal/toxic glycogen with shorter chains (phosphorylase limit dextrin, PLD) in skeletal and/or heart muscle and/or in the liver. Currently, there is no targeted therapy, and available treatments are symptomatic, relying on specific diets. Enzyme Replacement Therapy (ERT) might represent a potential therapeutic strategy for GSD III. Moreover, the single-gene nature of GSD III, the subcellular localization of GDE, and the type of affected tissues represent ideal conditions for exploring gene therapy approaches. Toward this direction, we designed a synthetic, codon-optimized cDNA encoding the human GDE. This gene yielded high amounts of soluble, enzymatically active protein in Escherichia coli. Moreover, when transfected in Human Embryonic Kidney cells (HEK-293), it successfully encoded a functional GDE. These results suggest that our gene or protein might complement the missing function in GSD III patients, opening the door to further exploration of therapeutic approaches for this disease.
2020-06-09 | Expression of a Functional Recombinant Human Glycogen Debranching Enzyme (hGDE) in N. benthamiana Plants and in Hairy Root Cultures.
Glycogen storage disease type III (GSDIII, Cori/Forbes disease) is a metabolic disorder due to the deficiency of the Glycogen Debranching Enzyme (GDE), a large monomeric protein (about 176 kDa) with two distinct enzymatic activities: 4-α-glucantransferase and amylo-α-1,6-glucosidase. Several mutations along the amylo-alpha-1,6-glucosidase,4-alphaglucanotransferase (Agl) gene are associated with loss of enzymatic activity. The unique treatment for GSDIII, at the moment, is based on diet. The potential of plants to manufacture exogenous engineered compounds for pharmaceutical purposes, from small to complex protein molecules such as vaccines, antibodies and other therapeutic/prophylactic entities, was shown by modern biotechnology through "Plant Molecular Farming". In an attempt to develop novel protein-based therapeutics for GSDIII, the Agl gene, encoding for the human GDE (hGDE) was engineered for expression as a histidinetagged GDE protein both in Nicotiana benthamiana plants by a transient expression approach, and in axenic hairy root in vitro cultures (HR) from Lycopersicum esculentum and Beta vulgaris. In both plant-based expression formats, the hGDE protein accumulated in the soluble fraction of extracts. The plant-derived protein was purified by affinity chromatography in native conditions showing glycogen debranching activity. These investigations will be useful for the design of a new generation of biopharmaceuticals based on recombinant GDE protein that might represent, in the future, a possible therapeutic option for GSDIII.
2020-02-06 | Neutropenia in glycogen storage disease Ib: outcomes for patients treated with granulocyte colony-stimulating factor.
Glycogen storage disease Ib (GSD Ib) is characterized by hepatomegaly, hypoglycemia, neutropenia, enterocolitis and recurrent bacterial infections. It is attributable to mutations in G6PT1, the gene for the glucose-6-phosphate transporter responsible for transport of glucose into the endoplasmic reticulum. Neutropenia in GSD Ib is now frequently treated with granulocyte colony-stimulating factor (G-CSF). We formed a cooperative group to review outcomes of the long-term treatment of GSD Ib patients treated with G-CSF. The study enrolled 103 patients (48 men and 55 women), including 47 currently adult patients. All of these patients were treated with G-CSF, starting at a median age of 3.8 years (range 0.04-33.9 years) with a median dose of 3.0 mcg/kg/day (range 0.01-93.1 mcg/kg/day) for a median of 10.3 years (range 0.01-29.3 years). Neutrophils increased in response to G-CSF in all patients (median values before G-CSF 0.2 × 10/l, on G-CSF 1.20 x 10/l). Treatment increased spleen size (before G-CSF, 47%, on treatment on G-CSF 76%), and splenomegaly was the dose-limiting adverse effect of treatment (pain and early satiety). Clinical observations and records attest to reduce frequency of infectious events and the severity of inflammatory bowel symptoms, but fever and recurrent infections remain a significant problem. In the cohort of patients followed carefully through the Severe Chronic Neutropenia International Registry, four patients have developed myelodysplasia or acute myeloid leukemia and we are aware of four other cases, (altogether seven on G-CSF, one never treated with G-CSF). Liver transplantation in five patients did not correct neutropenia. Four patients had hematopoietic stem cell transplantation; two adults and two children were transplanted; one adult and one child survived. GSD Ib is a complex disorder of glucose metabolism causing severe chronic neutropenia. G-CSF is effective to raise blood neutrophil counts and reduce fevers and infections in most patients. In conjunction with other therapies (salicylates, mesalamine sulfasalazine and prednisone), G-CSF ameliorates inflammatory bowel symptoms, but doses must be limited because it increases spleen size associated with abdominal pain.
2014-02-18 | Mouse model of glycogen storage disease type III
Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of the glycogen debranching enzyme (GDE), which is encoded by the Agl gene. GDE deficiency leads to the pathogenic accumulation of phosphorylase limit dextrin (PLD), an abnormal glycogen, in the liver, heart, and skeletal muscle. To further investigate the pathological mechanisms behind this disease and develop novel therapies to treat this disease, we generated a GDE-deficient mouse model by removing exons after exon 5 in the Agl gene. GDE reduction was confirmed by western blot and enzymatic activity assay. Histology revealed massive glycogen accumulation in the liver, muscle, and heart of the homozygous affected mice. Interestingly, we did not find any differences in the general appearance, growth rate, and life span between the wild-type, heterozygous, and homozygous affected mice with ad libitum feeding, except reduced motor activity after 50 weeks of age, and muscle weakness in both the forelimb and hind legs of homozygous affected mice by using the grip strength test at 62 weeks of age. However, repeated fasting resulted in decreased survival of the knockout mice. Hepatomegaly and progressive liver fibrosis were also found in the homozygous affected mice. Blood chemistry revealed that alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities were significantly higher in the homozygous affected mice than in both wild-type and heterozygous mice and the activity of these enzymes further increased with fasting. Creatine phosphokinase (CPK) activity was normal in young and adult homozygous affected mice. However, the activity was significantly elevated after fasting. Hypoglycemia appeared only at a young age (3 weeks) and hyperlipidemia was not observed in our model. In conclusion, with the exception of normal lipidemia, these mice recapitulate human GSD IIIa; moreover, we found that repeated fasting was detrimental to these mice. This mouse model will be useful for future investigation regarding the pathophysiology and treatment strategy of human GSD III.
gene therapies
2025-10-08 | Long-Term Correction of Murine Glycogen Storage Disease Type III by AAV-Mediated Gene Therapy Using an Immunotolerizing Dual Promoter to Express Bacterial Pullulanase.
We recently reported an innovative gene therapy approach for GSD III using a recombinant adeno-associated virus serotype 9 vector (AAV9-Dual-Pull) expressing a bacterial debranching enzyme (pullulanase) driven by a tandem dual promoter that consists of an immunotolerizing liver-specific promoter (LSP) and the ubiquitous CMV enhance/chicken β-actin (CB) promoter. In this follow-up study, we evaluated the long-term efficacy of this gene therapy in GSD IIIa mice. Three-month-old GSD IIIa mice were intravenously injected with AAV9-LSP-Pull or AAV9-Dual-Pull at the same dose (2.5 × 1013 vg/kg). Tissues were collected after 9 months for AAV genome quantification, pullulanase expression determination, and glycogen content measurement. Liver and muscle enzymes in plasma and disease biomarker in urine were analyzed at multiple time points to examine the correction of liver and muscle damage. Behavioral tests were performed during the course of AAV treatment to evaluate the improvement of muscle function. The AAV-Dual-Pull treatment led to persistent pullulanase expression and effective glycogen reduction in the liver, heart, and skeletal muscle, accompanied by the reversal of liver fibrosis, decrease of plasma enzyme activities, and long-term improvement of muscle function. The AAV-LSP-Pull treatment showed a better therapeutic efficacy in the liver but had no effect on the cardiac and skeletal muscles. Our results demonstrated the long-term efficacy and safety of systemic AAV9-Dual-Pull delivery in GSD IIIa mice. Future studies will test this gene therapy approach in GSD IIIa dogs prior to the clinical translation to GSD III patients.
2025-09-11 | High-potency MyoAAV capsids enhanced skeletal muscle correction in a mouse model of GSD IIIa.
Glycogen storage disease type IIIa (GSD IIIa) affects multiple tissues, including liver, heart, and skeletal muscles. We recently reported that an adeno-associated virus serotype 9 vector expressing pullulanase, a bacterial glycogen debranching enzyme, driven by an immunotolerizing dual promoter (AAV9-Dual-Pull), effectively decreased pullulanase-induced cytotoxic T lymphocyte response and corrected disease abnormalities in all major affected tissues in GSD IIIa mice. To reduce effective vector dosages for transgene delivery to skeletal muscles, we packaged the AAV-Dual-Pull vector into two muscle-tropic MyoAAV capsids, MyoAAV4A and MyoAAV4E. Six weeks after administration of the same dose vector (1 × 1013 vg/kg), both the MyoAAV vectors demonstrated remarkably greater transduction efficiency and glycogen clearance efficacy in the cardiac and skeletal muscles than the AAV9 vector, accompanied by the improvement of muscle function, reversal of liver abnormalities, and normalization of the disease biomarker, Glc4 in the urine. Furthermore, treatment with the MyoAAV4A-Dual-Pull vector at a 10-fold lower dose (1×1012 vg/kg) achieved significantly better therapeutic outcomes in the skeletal muscles than the AAV9-Dual-Pull vector at a high dose (1×1013 vg/kg). Validation in human liver chimeric mice revealed that the MyoAAV vectors and the AAV9 vectors had a similar efficiency in transducing human hepatocytes, indicating increased translatability for clinical applications.
2022-12-15 | Suppression of pullulanase-induced cytotoxic T cell response with a dual promoter in GSD IIIa mice.
Glycogen debranching enzyme deficiency in glycogen storage disease type III (GSD III) results in excessive glycogen accumulation in multiple tissues, primarily the liver, heart, and skeletal muscle. We recently reported that an adeno-associated virus vector expressing a bacterial debranching enzyme (pullulanase) driven by the ubiquitous CMV enhancer/chicken β-actin (CB) promoter cleared glycogen in major affected tissues of infant GSD IIIa mice. In this study, we developed a potentially novel dual promoter consisting of a liver-specific promoter (LSP) and the CB promoter for gene therapy in adult GSD IIIa mice. Ten-week treatment with an adeno-associated virus vector containing the LSP-CB dual promoter in adult GSD IIIa mice significantly increased pullulanase expression and reduced glycogen contents in the liver, heart, and skeletal muscle, accompanied by the reversal of liver fibrosis, improved muscle function, and a significant decrease in plasma biomarkers alanine aminotransferase, aspartate aminotransferase, and creatine kinase. Compared with the CB promoter, the dual promoter effectively decreased pullulanase-induced cytotoxic T lymphocyte responses and enabled persistent therapeutic gene expression in adult GSD IIIa mice. Future studies are needed to determine the long-term durability of dual promoter-mediated expression of pullulanase in adult GSD IIIa mice and in large animal models.
small molecules
2026-08-11 | High-Protein Diet Ameliorates Cardiomyopathy in a Cardiac-Specific AGL Knockout Mouse Model: Association With Upregulated Hepatic Gluconeogenesis.
Glycogen storage disease type IIIa (GSDIIIa) causes progressive cardiomyopathy, and current high-fat dietary strategies lack consensus regarding long-term cardiovascular safety. We evaluated the efficacy and safety of high-protein versus high-fat diets in a novel cardiac-specific AGL knockout (CKO; AGLflox/flox/MHC-Cre) mouse model to specifically assess isolated cardiac responses. CKO mice were randomized at weaning to High-Protein (HPD), High-Protein High-Fat (HPHFD), or Low-Protein (LPD) diets, with approximate protein/fat/carbohydrate distributions of 40%/4%/50%, 40%/50%/10%, and 10%/4%/80%, respectively; CKO mice on normal diet (ND) and AGLflox/flox mice served as controls. Cardiac phenotypes and hepatic gluconeogenic enzymes were evaluated longitudinally up to 24 weeks. CKO-ND mice developed progressive cardiomyopathy with elevated myocardial glycogen at 24 weeks (32.01 ± 3.22 vs. 5.90 ± 2.21 mg/g in controls, p < 0.001), reduced left ventricular ejection fraction, and elevated serum creatine kinase. Both HPD and HPHFD significantly reduced myocardial glycogen burden (12.82 ± 3.58 and 15.07 ± 4.40 mg/g, p < 0.001), restored systolic function, and normalized hypertrophy. However, HPHFD induced distinct hyperlipidemia, whereas HPD maintained a stable lipid profile. Furthermore, therapeutic benefits in high-protein groups were associated with upregulated hepatic rate-limiting gluconeogenic enzymes (FBP2, PCK1). In this cardiac-specific AGL knockout model, a high-protein, non-high-fat diet attenuated cardiac glycogen accumulation and systolic dysfunction without the hyperlipidemia observed with the high-fat regimen. These preclinical findings support further evaluation of high-protein dietary strategies for GSDIIIa cardiomyopathy and suggest a possible liver-heart metabolic axis involving hepatic gluconeogenesis.
2026-04-14 | Effects of Extended-Release Cornstarch Supplementation on Glycemic Stability and Metabolic Parameters in Korean Patients with Glycogen Storage Disease.
Background/Objectives: Patients with hepatic glycogen storage disease (GSD) require frequent nighttime intake of uncooked corn starch (UCCS) to prevent fasting hypoglycemia, which imposes a substantial burden. Glycosade, an extended-release cornstarch, was developed to prolong overnight glucose availability. However, data regarding South Korean patients are limited. Therefore, we aimed to evaluate the efficacy and safety of Glycosade in South Korean patients with hepatic GSD. Methods: In this single-center prospective observational study, patients with hepatic GSD underwent laboratory evaluations before and 1 month after Glycosade administration. Continuous glucose monitoring (CGM) was performed during UCCS and Glycosade administration periods. The nocturnal mean glucose, coefficient of variation, time in range (70-180 mg/dL), and time below the range (<70 and <54 mg/dL) were compared between the periods using paired analyses. Results: No significant differences were observed in the nocturnal CGM metrics between the treatment periods. However, time-aligned CGM profiles revealed distinct temporal patterns, with a decline in glucose levels approximately 3-4 h after UCCS intake, whereas Glycosade showed a more sustained glucose profile over an extended period. Liver enzyme and lipid levels improved significantly after 1 month of Glycosade supplementation. Conclusions: In a cohort of South Korean patients with hepatic GSD, Glycosade maintained nocturnal glycemic stability comparable to that of conventional cornstarch without increasing the risk of hypoglycemia. Glycosade was also associated with improved biochemical parameters, supporting its role in nighttime dietary management.
2026-04-02 | Bone mineral density assessment in pediatric patients with hepatic glycogen storage disease subtypes
Background: current scientific literature regarding bone mineral density (BMD) profiles in children with hepatic glycogen storage diseases (GSD) remains sparse. The underlying mechanisms of bone pathology in these patients are not yet fully elucidated. Primary contributors to BMD reduction in GSD include suboptimal metabolic control, mobilization of bone calcium and phosphates to compensate for metabolic shifts, hepatic dysfunction, muscular impairment, hypogonadism, and various micronutrient deficiencies. Aim: to investigate the correlations between BMD parameters and clinical, laboratory, and instrumental findings in pediatric patients with hepatic GSD subtypes. Materials and Methods: the study involved 72 patients aged 4 to 17 years (median age: 8.9 [6.7; 13.8]) diagnosed with GSD types I, III, VI, and IX. Lumbar spine BMD was evaluated using dual-energy X-ray absorptiometry (DXA). Multivariate linear regression was utilized to analyze the associations between variables. Results: the mean BMD Z-score for the entire cohort was within the physiological range (-0.13±1.3). However, 4% (n=3) of patients demonstrated reduced BMD relative to chronological age. A history of at least one fracture was noted in 19% (n=14) of cases, with 5% (n=4) resulting from low-energy trauma. The BMD Z-score showed a significant negative correlation with age (p=0.002) and serum levels of ALT (p=0.031), AST (p=0.028), and alkaline phosphatase (p=0.009). Conversely, positive associations were identified with height Z-score (p<0.001), acid-base status (p=0.02), HDL-cholesterol (p=0.034), glucose levels (p=0.088), and the presence of hepatic fibrosis (p=0.049). Increased fracture incidence was significantly associated with female sex (p=0.039) and liver fibrosis (p=0.02). Conclusion: advanced age, growth retardation (low height Z-score), metabolic disturbances (acidosis, hypoglycemia, dyslipidemia), hepatic cytolysis, and the presence of liver fibrosis represent significant risk factors for BMD reduction in pediatric hepatic GSD KEYWORDS: glycogen storage disease, pediatric patients, bone mineral density, osteoporosis, fractures, liver. FOR CITATION: Rakhmanina K.Yu., Tin I.F., Pavlovskaya E.V., Taran N.N., Bagaeva M.E., Abdulmanapova M.A., Zubovich A.I., Strokova T.V. Bone mineral density assessment in pediatric patients with hepatic glycogen storage disease subtypes. Russian Journal of Woman and Child Health. 2026;9(1):50–60 (in Russ.). DOI: 10.32364/2618-8430-2026-9-1-7
2026-03-09 | Hepatic Glycogen Storage Diseases in Brazil: A Multicenter Study.
To describe clinical and laboratory characteristics, emphasizing the evolution of patients with hepatic glycogen storage diseases (GSDs) followed in Brazilian reference centers. Multicenter, retrospective study involving 13 centers, using RedCap platform. 132 patients were included: 63 (47.8%) GSD type I (56 Ia, 7 Ib), 13 (9.8%) with type III (12 IIIa, 1 IIIb), 1 (0.8%) type IV, 6 (4.5%) type VI, and 49 (37.1%) with type IX (28 IXa, 7 IXb, and 14 IXc). Type I patients presented earlier (4 months) and had more episodes of hypoglycemia at clinical presentation (p < 0.001). Anthropometric data at admission revealed impaired growth, with a tendency toward short stature across the groups (median -2.06, -1.89, and -1.96 among type I, III, and IX respectively). The median body mass index (BMI) z-scores at admission for all three types were above +1. Only patients with type IX demonstrated significant improvement in height (p = 0.007) and BMI (p = 0.020) z-scores during follow-up. Regarding laboratory tests, significant decreases were observed in total cholesterol, triglycerides, venous lactate and aminotransferases in patients with types I and IX. Hepatic GSDs are heterogeneous diseases. There is a significant height impairment with a troublesome trend to overweight and obesity, especially in type I. Although there is improvement in aminotransferases, cholesterol, and triglycerides with follow-up, adherence to treatment remains a challenge.
2026-02-09 | Enhanced lysosomal glycogen breakdown is associated with liver tumorigenesis in glycogen storage disease type III.
Glycogen storage disease type III (GSDIII) is a rare metabolic disorder caused by mutations in the glycogen debranching enzyme (AGL), leading to hepatic glycogen accumulation, fibrosis and increased hepatocellular carcinoma (HCC) risk. This study investigates the metabolic mechanisms driving liver tumorigenesis in an Agl -/- model of GSDIII. Liver and tumor samples from 14-month-old Agl -/- and Agl +/+ mice, and liver biopsies from patients with GSDIII (n = 4), were analyzed using histological, biochemical and molecular approaches. Agl -/- mice recapitulated key features of GSDIII, including a 3.5-fold hepatic glycogen overload (p <0.001), and chronic liver disease. More than 30% of the animals developed liver tumors, associated with a 2.5-fold increase in alpha-fetoprotein levels (p <0.005). Despite marked reductions in glucose (7.5-fold, p <0.0001), glucose-6 phosphate (266-fold, p <0.0001), lactate (8-fold, p <0.005), cholesterol (1.9-fold, p <0.001) and triglyceride levels (6.2-fold, p <0.001) in the liver, glycaemia was maintained at around 87.0 ± 9.6 mg/dl after 6 h of fasting, through activated extrahepatic, but not hepatic, gluconeogenesis. Intriguingly, most tumors exhibited lower glycogen content than surrounding tissue (3.3-fold decrease, p <0.0001), which was associated with increased lysosomal alpha-acid glucosidase activity (19.5 ± 5.5 in tumor vs. 9.9 ± 2.0 mmol/h/mg in Agl -/- liver; p <0.0005) and the presence of glycophagosomes. PAS-negative staining in HCCs from patients with GSDIII supported these observations. Although YAP nuclear staining varied among tumors, the overall increase in YAP nuclear localization and CTGF expression suggests that inhibition of the Hippo/YAP pathway may contribute to tumorigenesis in GSDIII hepatocytes. In GSDIII, liver metabolism is characterized by the accumulation of structurally abnormal glycogen and a significant reduction of key energy substrates. In this metabolic context, enhanced lysosomal glycogen degradation may support tumor growth, highlighting a mechanistic link between glycogen metabolism and the development of liver cancer. This study provides novel insights into the metabolic dysregulations driving liver tumorigenesis in glycogen storage disease type III (GSDIII). Our findings reveal a potential link between abnormal glycogen accumulation and liver cancer, highlighting the pivotal role of lysosomal glycogen degradation in supporting tumor growth. These results are particularly important for researchers and clinicians working on metabolic liver diseases, as they suggest potential glycogen-targeting therapeutic strategies for GSDIII and other related liver disorders. Practically, they could guide future interventions aimed at modulating glycogen metabolism, offering new treatment avenues for patients with GSDIII at risk of hepatocellular carcinoma, while contributing to the broader understanding of metabolic dysregulation in cancer biology.
proteins
2025-07-02 | Molecular architecture and catalytic mechanism of human glycogen debranching enzyme.
Glycogen, a key branched glucose polymer, acts as a vital energy reservoir in mammalian cells, particularly during intense activity or fasting. The glycogen debranching enzyme (GDE) plays a key role in glycogen degradation by removing branches, ensuring efficient glucose release. Dysfunction of GDE leads to the accumulation of limit dextrin and is implicated in the pathogenesis of Glycogen Storage Disease Type III (GSD III). We present the cryo-EM structure of human GDE (hsGDE) at 3.23 Å resolution, providing molecular insights into its substrate selectivity and catalytic mechanism. Our study further investigates the molecular consequences of disease-associated mutations by correlating structural data with enzymatic activities of representative GSD III-causing variants. We discover that these mutations induce GSD III through diverse mechanisms, including significant reductions in enzymatic activity, and disruptions to the glycogen-bound region and overall structural integrity. The elucidation of these pathways not only advances our understanding of hsGDE's role in substrate recognition and catalysis but also illuminates the molecular pathology of GSD III. Our findings pave the way for the development of targeted therapeutic strategies for this disease.
2024-07-18 | A Functional Human Glycogen Debranching Enzyme Encoded by a Synthetic Gene: Its Implications for Glycogen Storage Disease Type III Management.
Glycogen Storage Disease type III (GSD III) is a metabolic disorder resulting from a deficiency of the Glycogen Debranching Enzyme (GDE), a large monomeric protein (approximately 170 kDa) with cytoplasmic localization and two distinct enzymatic activities: 4-α-glucantransferase and amylo-α-1,6-glucosidase. Mutations in the Agl gene, with consequent deficiency in GDE, lead to the accumulation of abnormal/toxic glycogen with shorter chains (phosphorylase limit dextrin, PLD) in skeletal and/or heart muscle and/or in the liver. Currently, there is no targeted therapy, and available treatments are symptomatic, relying on specific diets. Enzyme Replacement Therapy (ERT) might represent a potential therapeutic strategy for GSD III. Moreover, the single-gene nature of GSD III, the subcellular localization of GDE, and the type of affected tissues represent ideal conditions for exploring gene therapy approaches. Toward this direction, we designed a synthetic, codon-optimized cDNA encoding the human GDE. This gene yielded high amounts of soluble, enzymatically active protein in Escherichia coli. Moreover, when transfected in Human Embryonic Kidney cells (HEK-293), it successfully encoded a functional GDE. These results suggest that our gene or protein might complement the missing function in GSD III patients, opening the door to further exploration of therapeutic approaches for this disease.
2020-06-09 | Expression of a Functional Recombinant Human Glycogen Debranching Enzyme (hGDE) in N. benthamiana Plants and in Hairy Root Cultures.
Glycogen storage disease type III (GSDIII, Cori/Forbes disease) is a metabolic disorder due to the deficiency of the Glycogen Debranching Enzyme (GDE), a large monomeric protein (about 176 kDa) with two distinct enzymatic activities: 4-α-glucantransferase and amylo-α-1,6-glucosidase. Several mutations along the amylo-alpha-1,6-glucosidase,4-alphaglucanotransferase (Agl) gene are associated with loss of enzymatic activity. The unique treatment for GSDIII, at the moment, is based on diet. The potential of plants to manufacture exogenous engineered compounds for pharmaceutical purposes, from small to complex protein molecules such as vaccines, antibodies and other therapeutic/prophylactic entities, was shown by modern biotechnology through "Plant Molecular Farming". In an attempt to develop novel protein-based therapeutics for GSDIII, the Agl gene, encoding for the human GDE (hGDE) was engineered for expression as a histidinetagged GDE protein both in Nicotiana benthamiana plants by a transient expression approach, and in axenic hairy root in vitro cultures (HR) from Lycopersicum esculentum and Beta vulgaris. In both plant-based expression formats, the hGDE protein accumulated in the soluble fraction of extracts. The plant-derived protein was purified by affinity chromatography in native conditions showing glycogen debranching activity. These investigations will be useful for the design of a new generation of biopharmaceuticals based on recombinant GDE protein that might represent, in the future, a possible therapeutic option for GSDIII.
2020-02-06 | Neutropenia in glycogen storage disease Ib: outcomes for patients treated with granulocyte colony-stimulating factor.
Glycogen storage disease Ib (GSD Ib) is characterized by hepatomegaly, hypoglycemia, neutropenia, enterocolitis and recurrent bacterial infections. It is attributable to mutations in G6PT1, the gene for the glucose-6-phosphate transporter responsible for transport of glucose into the endoplasmic reticulum. Neutropenia in GSD Ib is now frequently treated with granulocyte colony-stimulating factor (G-CSF). We formed a cooperative group to review outcomes of the long-term treatment of GSD Ib patients treated with G-CSF. The study enrolled 103 patients (48 men and 55 women), including 47 currently adult patients. All of these patients were treated with G-CSF, starting at a median age of 3.8 years (range 0.04-33.9 years) with a median dose of 3.0 mcg/kg/day (range 0.01-93.1 mcg/kg/day) for a median of 10.3 years (range 0.01-29.3 years). Neutrophils increased in response to G-CSF in all patients (median values before G-CSF 0.2 × 10/l, on G-CSF 1.20 x 10/l). Treatment increased spleen size (before G-CSF, 47%, on treatment on G-CSF 76%), and splenomegaly was the dose-limiting adverse effect of treatment (pain and early satiety). Clinical observations and records attest to reduce frequency of infectious events and the severity of inflammatory bowel symptoms, but fever and recurrent infections remain a significant problem. In the cohort of patients followed carefully through the Severe Chronic Neutropenia International Registry, four patients have developed myelodysplasia or acute myeloid leukemia and we are aware of four other cases, (altogether seven on G-CSF, one never treated with G-CSF). Liver transplantation in five patients did not correct neutropenia. Four patients had hematopoietic stem cell transplantation; two adults and two children were transplanted; one adult and one child survived. GSD Ib is a complex disorder of glucose metabolism causing severe chronic neutropenia. G-CSF is effective to raise blood neutrophil counts and reduce fevers and infections in most patients. In conjunction with other therapies (salicylates, mesalamine sulfasalazine and prednisone), G-CSF ameliorates inflammatory bowel symptoms, but doses must be limited because it increases spleen size associated with abdominal pain.
2014-02-18 | Mouse model of glycogen storage disease type III
Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of the glycogen debranching enzyme (GDE), which is encoded by the Agl gene. GDE deficiency leads to the pathogenic accumulation of phosphorylase limit dextrin (PLD), an abnormal glycogen, in the liver, heart, and skeletal muscle. To further investigate the pathological mechanisms behind this disease and develop novel therapies to treat this disease, we generated a GDE-deficient mouse model by removing exons after exon 5 in the Agl gene. GDE reduction was confirmed by western blot and enzymatic activity assay. Histology revealed massive glycogen accumulation in the liver, muscle, and heart of the homozygous affected mice. Interestingly, we did not find any differences in the general appearance, growth rate, and life span between the wild-type, heterozygous, and homozygous affected mice with ad libitum feeding, except reduced motor activity after 50 weeks of age, and muscle weakness in both the forelimb and hind legs of homozygous affected mice by using the grip strength test at 62 weeks of age. However, repeated fasting resulted in decreased survival of the knockout mice. Hepatomegaly and progressive liver fibrosis were also found in the homozygous affected mice. Blood chemistry revealed that alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities were significantly higher in the homozygous affected mice than in both wild-type and heterozygous mice and the activity of these enzymes further increased with fasting. Creatine phosphokinase (CPK) activity was normal in young and adult homozygous affected mice. However, the activity was significantly elevated after fasting. Hypoglycemia appeared only at a young age (3 weeks) and hyperlipidemia was not observed in our model. In conclusion, with the exception of normal lipidemia, these mice recapitulate human GSD IIIa; moreover, we found that repeated fasting was detrimental to these mice. This mouse model will be useful for future investigation regarding the pathophysiology and treatment strategy of human GSD III.
gene therapies
2025-10-08 | Long-Term Correction of Murine Glycogen Storage Disease Type III by AAV-Mediated Gene Therapy Using an Immunotolerizing Dual Promoter to Express Bacterial Pullulanase.
We recently reported an innovative gene therapy approach for GSD III using a recombinant adeno-associated virus serotype 9 vector (AAV9-Dual-Pull) expressing a bacterial debranching enzyme (pullulanase) driven by a tandem dual promoter that consists of an immunotolerizing liver-specific promoter (LSP) and the ubiquitous CMV enhance/chicken β-actin (CB) promoter. In this follow-up study, we evaluated the long-term efficacy of this gene therapy in GSD IIIa mice. Three-month-old GSD IIIa mice were intravenously injected with AAV9-LSP-Pull or AAV9-Dual-Pull at the same dose (2.5 × 1013 vg/kg). Tissues were collected after 9 months for AAV genome quantification, pullulanase expression determination, and glycogen content measurement. Liver and muscle enzymes in plasma and disease biomarker in urine were analyzed at multiple time points to examine the correction of liver and muscle damage. Behavioral tests were performed during the course of AAV treatment to evaluate the improvement of muscle function. The AAV-Dual-Pull treatment led to persistent pullulanase expression and effective glycogen reduction in the liver, heart, and skeletal muscle, accompanied by the reversal of liver fibrosis, decrease of plasma enzyme activities, and long-term improvement of muscle function. The AAV-LSP-Pull treatment showed a better therapeutic efficacy in the liver but had no effect on the cardiac and skeletal muscles. Our results demonstrated the long-term efficacy and safety of systemic AAV9-Dual-Pull delivery in GSD IIIa mice. Future studies will test this gene therapy approach in GSD IIIa dogs prior to the clinical translation to GSD III patients.
2025-09-11 | High-potency MyoAAV capsids enhanced skeletal muscle correction in a mouse model of GSD IIIa.
Glycogen storage disease type IIIa (GSD IIIa) affects multiple tissues, including liver, heart, and skeletal muscles. We recently reported that an adeno-associated virus serotype 9 vector expressing pullulanase, a bacterial glycogen debranching enzyme, driven by an immunotolerizing dual promoter (AAV9-Dual-Pull), effectively decreased pullulanase-induced cytotoxic T lymphocyte response and corrected disease abnormalities in all major affected tissues in GSD IIIa mice. To reduce effective vector dosages for transgene delivery to skeletal muscles, we packaged the AAV-Dual-Pull vector into two muscle-tropic MyoAAV capsids, MyoAAV4A and MyoAAV4E. Six weeks after administration of the same dose vector (1 × 1013 vg/kg), both the MyoAAV vectors demonstrated remarkably greater transduction efficiency and glycogen clearance efficacy in the cardiac and skeletal muscles than the AAV9 vector, accompanied by the improvement of muscle function, reversal of liver abnormalities, and normalization of the disease biomarker, Glc4 in the urine. Furthermore, treatment with the MyoAAV4A-Dual-Pull vector at a 10-fold lower dose (1×1012 vg/kg) achieved significantly better therapeutic outcomes in the skeletal muscles than the AAV9-Dual-Pull vector at a high dose (1×1013 vg/kg). Validation in human liver chimeric mice revealed that the MyoAAV vectors and the AAV9 vectors had a similar efficiency in transducing human hepatocytes, indicating increased translatability for clinical applications.
2022-12-15 | Suppression of pullulanase-induced cytotoxic T cell response with a dual promoter in GSD IIIa mice.
Glycogen debranching enzyme deficiency in glycogen storage disease type III (GSD III) results in excessive glycogen accumulation in multiple tissues, primarily the liver, heart, and skeletal muscle. We recently reported that an adeno-associated virus vector expressing a bacterial debranching enzyme (pullulanase) driven by the ubiquitous CMV enhancer/chicken β-actin (CB) promoter cleared glycogen in major affected tissues of infant GSD IIIa mice. In this study, we developed a potentially novel dual promoter consisting of a liver-specific promoter (LSP) and the CB promoter for gene therapy in adult GSD IIIa mice. Ten-week treatment with an adeno-associated virus vector containing the LSP-CB dual promoter in adult GSD IIIa mice significantly increased pullulanase expression and reduced glycogen contents in the liver, heart, and skeletal muscle, accompanied by the reversal of liver fibrosis, improved muscle function, and a significant decrease in plasma biomarkers alanine aminotransferase, aspartate aminotransferase, and creatine kinase. Compared with the CB promoter, the dual promoter effectively decreased pullulanase-induced cytotoxic T lymphocyte responses and enabled persistent therapeutic gene expression in adult GSD IIIa mice. Future studies are needed to determine the long-term durability of dual promoter-mediated expression of pullulanase in adult GSD IIIa mice and in large animal models.
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Drug Discovery Landscape
2 orphan drug designations for Glycogen storage disease due to glycogen debranching enzyme deficiency.
2 orphan drug designations for Glycogen storage disease due to glycogen debranching enzyme deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
mRNA encoding the human glycogen debranching enzyme | gene therapies | EMA | 2021-07-19 | — | Ultragenyx Germany GmbH |
mRNA encoding the human glycogen debranching enzyme | RNAs | FDA | 2021-06-24 | — | Ultragenyx Pharmaceutical Inc. |
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