RARE DISEASE
Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia
Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia
Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia
Synonyms: G6P deficiency type 1a, GSD due to G6P deficiency type 1a, GSD due to G6P deficiency type Ia, GSD type 1a, GSDIa, Glycogen storage disease due to G6P deficiency type Ia, Glycogen storage disease type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type Ia, Glycogenosis type Ia
Synonyms: G6P deficiency type 1a, GSD due to G6P deficiency type 1a, GSD due to G6P deficiency type Ia, GSD type 1a, GSDIa, Glycogen storage disease due to G6P deficiency type Ia, Glycogen storage disease type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type Ia, Glycogenosis type Ia
Synonyms: G6P deficiency type 1a, GSD due to G6P deficiency type 1a, GSD due to G6P deficiency type Ia, GSD type 1a, GSDIa, Glycogen storage disease due to G6P deficiency type Ia, Glycogen storage disease type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type Ia, Glycogenosis type Ia
Drug discovery
5
drugs
With orphan designations
Overview
Glycogen Storage Disease Type Ia (GSD Ia) is a rare autosomal recessive disorder caused by G6PC gene mutations, leading to glucose-6-phosphatase deficiency. This impairs glycogenolysis and gluconeogenesis, resulting in fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, and hyperlipidemia. Chronic complications include hepatic adenomas, renal dysfunction, and osteoporosis. Diagnosis typically occurs in infancy (3–4 months) with hypoglycemic seizures and hepatomegaly. Management focuses on dietary glucose stabilization, though complications persist despite treatment [1][4][12][15].
Burden
Physical: Progressive liver/kidney damage, adenoma risk (25–75% of adults), anemia, and osteoporosis [2][8][12].
Metabolic: Lifelong hypoglycemia risk, requiring strict dietary adherence [7][15].
Psychosocial: High caregiver burden, anxiety, and reduced quality of life due to dietary rigidity and monitoring demands [7][16].
Therapies
Dietary: Frequent carbohydrate intake, nocturnal enteral feeds, and uncooked cornstarch (UCCS) to prevent hypoglycemia [3][8][20].
Pharmacologic: Allopurinol (hyperuricemia), statins (dyslipidemia), ACE inhibitors (renal protection) [8][12].
Emerging Therapies: Phase III trials for AAV8-mediated gene therapy (NCT05139316) and mRNA therapy (NCT05095727) [10][13][16].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare renal diseases, rare transplant-related disorders
Research Papers
224 drug discovery papers about Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia, with 4 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
224 drug discovery papers about Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia, with 4 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | Bempedoic Acid Treatment in Four Adult Patients with Glycogen Storage Disease Type 1a: A Retrospective, Exploratory Case Series
Background: Glycogen storage disease type 1a (GSD 1a) is an inborn error of metabolism due to glucose-6-phosphatase deficiency. Treatment consists of frequent, carbohydrate-rich meals, intake of glucose polymers like uncooked cornstarch, or drip feeding in small infants. Although dietary treatment is challenging, it has improved the long-term outcomes for patients with GSD 1a. Nevertheless, several complications, including dyslipidaemia, remain difficult to manage, and early atherosclerosis with risk for ischemic stroke is a potential long-term concern. We propose bempedoic acid (BA) as a potential treatment option for dyslipidaemia in adult patients with GSD 1a. BA is an approved lipid-lowering therapy and may have additional beneficial metabolic effects in patients with GSD 1a. We hypothesize that BA may reduce malonyl-CoA concentrations and thereby alleviate the inhibition of mitochondrial fatty acid oxidation. This could potentially contribute to improved metabolic stability in patients with GSD 1a. Methods: Four adult female patients with GSD 1a and dyslipidaemia received BA at a dose of 180 mg once daily for 2–5 years. In this retrospective case series, we explored potential additional effects of BA treatment beyond its established lipid-lowering effect. Results: Under BA treatment, patients reported prolonged fasting periods, and carbohydrate intake could be reduced in some patients. Plasma lactate concentrations decreased during treatment, while triglyceride concentrations decreased in two patients but increased in the others. Two patients experienced a slight, clinically irrelevant increase in serum uric acid concentrations, a known adverse effect of BA. No other adverse effects were observed. Conclusions: In this retrospective, uncontrolled, single-center case series, BA was associated not only with its expected lipid-lowering effect, but also with potential improvements in metabolic control and prolonged fasting tolerance in adults with GSD 1a. However, these preliminary observations require confirmation in larger, prospective, controlled studies. Future studies should include standardized metabolic assessments and direct measurements of key metabolites involved in the pathophysiology of GSD 1a. Preclinical studies using appropriate animal models may further contribute to elucidating the underlying mechanisms and potential metabolic effects of BA.
2026-09-15 | Generation of a glycogen storage disease mouse model with fatty liver and its treatment by PPAR-α agonist bezafibrate.
Fatty liver is considered the pathological basis for the development of glycogen storage disease type Ia (GSDIa); however, due to the lack of suitable animal models, the mechanism underlying fatty liver development in GSDIa is largely unknown. This study employed surrogate breastfeeding to enable the survival of glucose-6-phosphatase catalytic (G6PC) knockout (KO) mice into adulthood, and then analyzed fatty liver phenotypes in 3-month-old KO (KO-3), 6-month-old KO (KO-6), and 9-month-old KO (KO-9) mice. KO-6 and KO-9 mice exhibited typical fatty liver phenotypes, and upregulation of glucose-6-phosphate (G6P). Moreover, both Western blot and qRT-PCR analysis showed significant upregulation of ChREBP, SREBP1 and fatty acid synthesis enzymes. RNA-seq heat maps revealed that KO-6 and KO-9 mice exhibited similar expression patterns, distinct from those observed in the wild-type (WT) and KO-3 groups. GO and KEGG analysis further revealed changes in lipid metabolism pathways in KO-6 and KO-9 mice, as well as PI3K-Akt, AMPK, and MAPK signaling. Western blot analysis showed that the Akt and mTOR pathways were activated, while the AMPK pathway was downregulated, indicating impaired autophagy. Finally, bezafibrate, a proliferator-activated receptor α (PPAR-α) agonist, enhanced autophagic activity and attenuated inflammatory responses, fat deposition, and glycogen storage in G6PC KO mice. This study successfully generated a fatty liver model using G6PC KO adult mice and demonstrated that pharmacological activation of PPAR-α may have therapeutic potential in adult G6PC KO mice.
2026-09-02 | Continuous glucose monitoring–guided optimization of peritoneal dialysis prescription in glycogen storage disease type 1a: a case report
Abstract Background Glycogen storage disease type 1a (GSD-1a) is a rare inherited metabolic disorder characterized by impaired glucose homeostasis and progressive renal involvement. As life expectancy has improved, an increasing number of patients develop end-stage kidney disease (ESKD); however, optimal renal replacement therapy (RRT) strategies remain unclear. Case presentation We report a 48-year-old man with GSD-1a who progressed to ESKD and underwent initiation of peritoneal dialysis (PD). Despite dietary management, he experienced recurrent nocturnal hypoglycemia. Continuous glucose monitoring (CGM) was used to evaluate glucose profiles under different PD modalities. Intermittent PD without nocturnal dialysate dwelling and continuous ambulatory PD were insufficient to prevent nocturnal hypoglycemia. Switching to nightly intermittent PD enabled continuous nocturnal glucose absorption from dialysate exchanges, resulting in the resolution of nocturnal hypoglycemia without the need for late-night snacks. Conclusion This case demonstrates that CGM can be a useful tool not only for detecting asymptomatic hypoglycemia but also for individualizing PD prescription in patients with GSD-1a. Individualized RRT strategies based on metabolic characteristics may improve safety and quality of life in this rare population.
2026-03-20 | Infantile extreme hypertriglyceridemia diagnosed as glycogen storage disease type Ia: A case report.
Glycogen storage disease type Ia (GSD Ia) typically presents with fasting hypoglycemia and hyperlipidemia. Atypical infantile presentations can delay diagnosis. We report an infant with extreme hypertriglyceridemia ultimately diagnosed as GSD Ia. A 5-month-old girl presented with poor appetite, growth retardation, hepatomegaly, and extreme hypertriglyceridemia (72 mmol/L), hypercholesterolemia, elevated transaminases, hyperuricemia, and hyperlactatemia, but initial normal blood glucose. Initial differentials included familial hypertriglyceridemia, but metabolic screening was normal. Whole-exome sequencing confirmed GSD Ia with compound heterozygous G6PC mutations (c.648G>T and c.814G>T). Initial lipid-lowering (low-fat diet, fenofibrate, omega-3, plasma exchange) reduced triglyceride. Post-diagnosis, she received lactose-free formula with frequent feeds and nocturnal nutrition; uncooked cornstarch was introduced at 6 months, though adherence was initially poor. Metabolic control was unstable until age 2 due to poor adherence. After 24 months of structured cornstarch therapy, fasting glucose normalized (4.2-6.6 mmol/L), triglycerides decreased (1.8-6.7 mmol/L), and catch-up growth occurred (height Z-score from -3.9 to -2.2 by 36 months). GSD Ia should be considered in infantile extreme hypertriglyceridemia with growth retardation, even without classic hypoglycemia. Sustained metabolic control requires multidisciplinary strategies addressing both biochemical and adherence barriers.
2026-01-01 | Continuous Glucose Monitoring–Driven Personalization of Cornstarch Therapy in Glycogen Storage Disease: A Retrospective Analysis
PURPOSE: Hepatic glycogen storage diseases (GSD), including types Ia, Ib, and IXa, are rare inherited disorders characterized by impaired hepatic glucose homeostasis. In GSD Ia, deficiency of glucose-6-phosphatase results in recurrent hypoglycemia and metabolic disturbances. Uncooked cornstarch (UCCS) is the standard therapy due to its slow digestion and sustained glucose release; however, dosing requirements vary according to age, digestion rate, metabolic demand, and lifestyle. Despite the central role of UCCS in long-term management, real-world data describing extended continuous glucose monitoring (CGM) patterns in hepatic GSD are extremely limited, and objective evidence guiding individualized dose adjustment remains scarce. This study examined CGM profiles in patients with hepatic GSD receiving long-term UCCS therapy and assessed the clinical utility of CGM in guiding individualized dosing adjustments. MATERIALS AND METHODS: We performed a retrospective, multi-year analysis of CGM data from 32 patients with hepatic GSD treated with UCCS. CGM traces were processed using 15-minute resampling, constrained interpolation, and physiologic clipping (40-400 mg/dL). Data were segmented into non-overlapping, calendar-anchored 7- and 14-day windows (anchor at 00:00) and retained when coverage was ≥70%. Per window, we calculated time in range (TIR, 70-150 mg/dL), time below range (TBR, <70 mg/dL), time above range (≥150 mg/dL), coefficient of variation, nocturnal TBR (00:00-06:00), and hypoglycemia burden [area under the curve (AUC) <70 mg/dL]. RESULTS: During routine clinic follow-up, CGM-informed, patient-specific UCCS and dietary adjustments maintained high TIR and low glycemic variability. Growth parameters and liver enzyme levels remained within normal limits. Episodes of recurrent nocturnal hypoglycemia identified on CGM prompted targeted modifications of UCCS dosing. CONCLUSION: A CGM-guided approach facilitates personalized UCCS management in hepatic GSD. Systematic review of TIR, nocturnal TBR, and AUC <70 mg/dL, alongside growth and liver assessments, provides a practical framework for optimizing long-term metabolic stability.
cell therapies
2026-08-28 | Simultaneous Liver-Kidney Transplantation from a Deceased Donor for Glycogen Storage Disease Type Ia: A Case Report.
Glycogen storage disease type Ia (GSD Ia) is an indication for simultaneous liver-kidney transplantation (SLKT) due to multiple hepatocellular adenomas and chronic renal failure. In this report, we describe a deceased-donor SLKT in a patient with GSD Ia who presented with hypoglycemic attacks, progressive multiple hepatocellular adenomas, and chronic renal failure. The patient was diagnosed with hepatomegaly at the age of 1 year and 6 months, with a diagnosis of GSD Ia, and was started on a special diet. She had been aware of liver tumors since 24 years of age. At 29 years of age, she underwent left lateral segmentectomy and radiofrequency ablation for multiple liver tumors. She began to suffer from renal dysfunction around 39 years of age, and then at 40 years of age, she was diagnosed with chronic renal failure and therefore was started on hemodialysis. She began having recurrent hypoglycemic attacks after the introduction of dialysis. Due to repeated hypoglycemic attacks, multiple hepatocellular adenomas, and chronic renal failure, she was deemed eligible for SLKT and thus was registered for deceased-donor SLKT at 41 years of age. She underwent SLKT at 46 years of age. The liver graft weight was 1060 g, and the graft-to-recipient body weight ratio was 2.41. The kidney graft weight was 170 g. The weight of the excised liver was 2710 g. Although no malignant findings were observed in the excised liver, multiple hepatocellular adenomas were identified. She was able to urinate independently immediately after the SLKT and was able to discontinue dialysis immediately afterward. Immunosuppressive therapy was initiated with basiliximab, ciclosporin A, methylprednisolone, and mycophenolate mofetil (MMF). However, due to abdominal pain and liver dysfunction caused by MMF, she was switched to mizoribine on POD 46, and her abdominal pain improved thereafter. She progressed well and was discharged on POD 49. Her liver and kidney functions remained good approximately 2 years after the SLKT. Adult patients with GSD Ia require transplantation due to hypoglycemic attacks, multiple liver tumors, and chronic renal failure.
2025-08-30 | Liver Transplantation as a Metabolic Treatment in Glycogen Storage Disease Type Ia.
Glycogen storage disease type Ia (GSD Ia) is a rare autosomal recessive metabolic disorder characterized by glucose-6-phosphatase deficiency, leading to severe fasting hypoglycemia, hypertriglyceridemia, hyperuricemia, hepatic adenomas, and osteoporosis. While intensive dietary and pharmacologic therapy remains the cornerstone of treatment, a subset of patients fails to achieve metabolic control and develops life-altering complications. We report the case of a 20-year-old male with genetically confirmed GSD Ia who exhibited persistent hypoglycemia, severe hyperlipidemia, hepatic adenomas, and osteoporosis despite optimal medical management. Due to the progression of hepatic and systemic complications, the patient underwent living donor liver transplantation using his father as the donor. Posttransplant follow-up demonstrated complete resolution of metabolic abnormalities, including hypoglycemia and dyslipidemia, normalization of liver function tests, and significant improvement in bone mineral density and quality of life. This case highlights the role of liver transplantation as a definitive metabolic treatment in selected patients with GSD Ia, offering not only biochemical correction but also prevention of neoplastic transformation and reversal of skeletal complications.
2014-11-04 | Biodistribution of adult derived human liver stem cells following intraportal infusion in a 17-year-old patient with glycogenosis type 1A.
Current treatment of inherited liver inborn errors of metabolism in children consists in appropriate diet and drugs and, for unstable patients, final orthotopic liver transplantation. Unfortunately, liver transplantation remains not easily available because of organ shortage and imposes inherent risks and lifelong immunosuppressive therapy. Therefore alternative treatments are required. Hepatocytes transplantation and its limitations led to consider innovative alternative such as transplantation of adult derived human liver stem cells (ADLHSC). These cells present high proliferative capacity, good resistance to cryopreservation and ability to differentiate into hepatocyte-like cells displaying mature hepatocyte functions. Biodistribution of ADHLSC had never been assessed after infusion through the portal vein in patients. This information is required to determine the safety of the method. ADHLSC were efficiently labelled with 111-Indium DTPA radiotracer and SPECT imaging was used for the acquisition of whole body imaging to document short term biodistribution of ADHLSC. Following infusion through the portal vein, ADHLSC diffused homogenously throughout the liver and remained strictly within the targeted organ. Images were acquired until 5 days after infusion. At that time, no signal was observed in any other organs except the liver. Urinary excretion of 111-Indium DTPA was also monitored. For the first time, we documented the short term biodistribution of ADHLSC within the liver after infusion through the portal vein.
2014-08-28 | Lessons from new mouse models of glycogen storage disease type 1a in relation to the time course and organ specificity of the disease
Patients with glycogen storage diseases type 1 (GSD1) suffer from life-threatening hypoglycaemia, when left untreated. Despite an intensive dietary treatment, patients develop severe complications, such as liver tumors and renal failure, with aging. Until now, the animal models available for studying the GSD1 did not survive after weaning. To gain further insights into the molecular mechanisms of the disease and to evaluate potential treatment strategies, we have recently developed novel mouse models in which the catalytic subunit of glucose-6 phosphatase (G6pc) is deleted in each glucose-producing organ specifically. For that, B6.G6pc(ex3lox/ex3lox) mice were crossed with transgenic mice expressing a recombinase under the control of the serum albumin, the kidney androgen protein or the villin promoter, in order to obtain liver, kidney or intestine G6pc(-/-) mice, respectively. As opposed to total G6pc knockout mice, tissue-specific G6pc deficiency allows mice to maintain their blood glucose by inducing glucose production in the other gluconeogenic organs. Even though it is considered that glucose is produced mainly by the liver, liver G6pc(-/-) mice are perfectly viable and exhibit the same hepatic pathological features as GSD1 patients, including the late development of hepatocellular adenomas and carcinomas. Interestingly, renal G6pc(-/-) mice developed renal symptoms similar to the early human GSD1 nephropathy. This includes glycogen overload that leads to nephromegaly and morphological and functional alterations in the kidneys. Thus, our data suggest that renal G6Pase deficiency per se is sufficient to induce the renal pathology of GSD1. Therefore, these new mouse models should allow us to improve the strategies of treatment on both nutritional and pharmacological points of view.
2014-04-09 | Liver transplantation in glycogen storage disease type I
Glycogen storage disease type I (GSDI), an inborn error of carbohydrate metabolism, is caused by defects in the glucose-6-transporter/glucose-6-phosphatase complex, which is essential in glucose homeostasis. Two types exist, GSDIa and GSDIb, each caused by different defects in the complex. GSDIa is characterized by fasting intolerance and subsequent metabolic derangements. In addition to these clinical manifestations, patients with GSDIb suffer from neutropenia with neutrophil dysfunction and inflammatory bowel disease. With the feasibility of novel cell-based therapies, including hepatocyte transplantations and liver stem cell transplantations, it is essential to consider long term outcomes of liver replacement therapy. We reviewed all GSDI patients with liver transplantation identified in literature and through personal communication with treating physicians. Our review shows that all 80 GSDI patients showed improved metabolic control and normal fasting tolerance after liver transplantation. Although some complications might be caused by disease progression, most complications seemed related to the liver transplantation procedure and subsequent immune suppression. These results highlight the potential of other therapeutic strategies, like cell-based therapies for liver replacement, which are expected to normalize liver function with a lower risk of complications of the procedure and immune suppression.
oligonucleotides
2023-12-04 | A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T.
Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-α (G6Pase-α, encoded by G6PC), which is primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves life expectancy, patients still experience intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a but potentially require complicated glycemic management throughout life. Here, we present an oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. We generated a mouse strain with homozygous knockin of this variant that well reflected the pathophysiology of patients with GSD1a. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b had long-lasting efficacy of more than 12 weeks in mice that received a single dose and had favorable pharmacokinetics and tolerability in mice and monkeys. These findings together indicate that this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.
2019-06-26 | Inhibition of Glycogen Synthase II with RNAi Prevents Liver Injury in Mouse Models of Glycogen Storage Diseases.
Glycogen storage diseases (GSDs) of the liver are devastating disorders presenting with fasting hypoglycemia as well as hepatic glycogen and lipid accumulation, which could lead to long-term liver damage. Diet control is frequently utilized to manage the potentially dangerous hypoglycemia, but there is currently no effective pharmacological treatment for preventing hepatomegaly and concurrent liver metabolic abnormalities, which could lead to fibrosis, cirrhosis, and hepatocellular adenoma or carcinoma. In this study, we demonstrate that inhibition of glycogen synthesis using an RNAi approach to silence hepatic Gys2 expression effectively prevents glycogen synthesis, glycogen accumulation, hepatomegaly, fibrosis, and nodule development in a mouse model of GSD III. Mechanistically, reduction of accumulated abnormally structured glycogen prevents proliferation of hepatocytes and activation of myofibroblasts as well as infiltration of mononuclear cells. Additionally, we show that silencing Gys2 expression reduces hepatic steatosis in a mouse model of GSD type Ia, where we hypothesize that the reduction of glycogen also reduces the production of excess glucose-6-phosphate and its subsequent diversion to lipid synthesis. Our results support therapeutic silencing of GYS2 expression to prevent glycogen and lipid accumulation, which mediate initial signals that subsequently trigger cascades of long-term liver injury in GSDs.
2013-06-10 | Enhanced gene expression of systemically administered plasmid DNA in the liver with therapeutic ultrasound and microbubbles.
Ultrasound-mediated delivery (USMD) of novel therapeutic agents in the presence of microbubbles is a potentially safe and effective method for gene therapy offering many desired characteristics, such as low toxicity, potential for repeated treatment, and organ specificity. In this study, we tested the capability of USMD to improve gene expression in mice livers using glycogen storage disease Type Ia as a model disease under systemic administration of naked plasmid DNA. Image-guided therapeutic ultrasound was used in two studies to provide therapeutic ultrasound to mice livers. In the first study, involving wild-type mice, control animals received naked plasmid DNA (pG6Pase 150 μg) via the tail vein, followed by an infusion of microbubbles; the treated animals additionally received therapeutic ultrasound (1 MHz). Following the procedure, the animals were left to recover and were subsequently euthanized after 2 d and liver samples were extracted. Reverse transcription polymerase chain reaction (RT-PCR) assays were performed on the samples to quantify mRNA expression. In addition, Western blot assays of FLAG-tagged glucose-6-phosphatase (G6Pase) were performed to evaluate protein expression. Ultrasound-exposed animals showed a 4-fold increase in G6Pase RNA in the liver, in comparison with control animals. Furthermore, results from Western blot analysis demonstrated a 2-fold increased protein expression in ultrasound-exposed animals after two days ( p < 0.05). A second pilot study was performed with G6Pase knockout mice, and the animals were monitored for correction of hypoglycemia over a period of 3 weeks before tissue analysis. The RT-PCR assays of samples from these animals demonstrated increased G6Pase RNA in the liver following ultrasound treatment. These results demonstrate that USMD can increase gene expression of systemically injected naked pDNA in the liver and also provide insight into the development of realistic approaches that can be translated into clinical practice.
2012-10-04 | Acoustically accessible window determination for ultrasound mediated treatment of glycogen storage disease type Ia patients
Glycogen storage disease type Ia (GSDIa) is caused by an inherited single-gene defect resulting in an impaired glycogen to glucose conversion pathway. Targeted ultrasound mediated delivery (USMD) of plasmid DNA (pDNA) to liver in conjunction with microbubbles may provide a potential treatment for GSDIa patients. As the success of USMD treatments is largely dependent on the accessibility of the targeted tissue by the focused ultrasound beam, this study presents a quantitative approach to determine the acoustically accessible liver volume in GSDIa patients. Models of focused ultrasound beam profiles for transducers of varying aperture and focal lengths were applied to abdomen models reconstructed from suitable CT and MRI images. Transducer manipulations (simulating USMD treatment procedures) were implemented via transducer translations and rotations with the intent of targeting and exposing the entire liver to ultrasound. Results indicate that acoustically accessible liver volumes can be as large as 50% of the entire liver volume for GSDIa patients and on average 3 times larger compared to a healthy adult group due to GSDIa patients' increased liver size. Detailed descriptions of the evaluation algorithm, transducer-and abdomen models are presented, together with implications for USMD treatments of GSDIa patients and transducer designs for USMD applications.
2011-07-24 | Acoustic Accessibility Investigation for Ultrasound Mediated Treatment of Glycogen Storage Disease Type Ia Patients
Glycogen storage disease type Ia (GSDIa) is caused by an inherited defect in the glucose-6-phosphatase gene. The recent advent of targeted ultrasound-mediated delivery (USMD) of plasmid DNA (pDNA) to the liver in conjunction with microbubbles may provide an alternative treatment option. This study focuses on determining the acoustically accessible liver volume in GSDIa patients using transducer models of various geometries with an image-based geometry-driven approach. Results show that transducers with longer focal lengths and smaller apertures (up to an f/number of 2) are able to access larger liver volumes in GSDIa patients while still being capable of delivering the required ultrasound dose in situ (2.5 MPa peak negative pressure at the focus). With sufficiently large acoustic windows and the ability to use glucose to easily assess efficacy, GSD appears to be a good model for testing USMD as proof of principle as a potential therapy for liver applications in general.
gene therapies
2026-09-08 | Genome Editing for Glycogen Storage Diseases.
Gene therapy has been developed for several glycogen storage diseases and has advanced into clinical trials. However, the limitations of these gene therapies with regard to stability following treatment early in life have led to the development of genome editing. Early results for genome editing in both glycogen storage disease type Ia and Pompe disease have demonstrated promising efficacy, and proof-of-concept studies as well as a clinical trial are underway. These studies will determine whether genome editing fulfills its promise with regard to stably treating glycogen storage diseases early in life.
2026-08-31 | Phase 3 Randomized Trial Results of DTX401 AAV Gene Therapy for the Treatment of GSDIa.
Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening inherited carbohydrate metabolism disorder caused by biallelic pathogenic G6PC gene variants resulting in deficiency of glucose-6-phosphatase. DTX401 is an investigational AAV8 vector containing the human G6PC gene. DTX401-CL301 is a pivotal, phase 3, double-blind, randomized, placebo-controlled trial of DTX401 in patients ≥ 8 years with GSDIa. The primary endpoint was percent change from Baseline to Week 48 in daily cornstarch intake for the DTX401 versus placebo group. Participants were randomly assigned (1:1) to blinded DTX401 or placebo. After the 48-week Primary Efficacy Analysis Period (PEAP), participants crossed over in a blinded manner for an additional 48-week blinded Crossover Period. Following randomization: 21 participants received DTX401; 25 received placebo. At Week 48, DTX401 treatment resulted in a statistically significant least squares (LS) mean (SE) daily cornstarch intake reduction of 41% (4.6) versus 10% (4.1) for Placebo (p < 0.0001). Clinical meaningfulness was evidenced by a mean desired percent reduction in daily cornstarch intake among those reporting in Baseline interviews (n = 33) of 45% (median = 41%). Greater and faster reductions in cornstarch were observed at Week 96 for the Crossover DTX401 group compared with the DTX401 group in the PEAP. The DTX401 safety profile was acceptable, and expected hepatic reactions consisting of transaminase elevations were managed with prophylactic corticosteroids. Treatment with DTX401 resulted in both a statistically significant and clinically meaningful reduction in cornstarch intake in the 48-week PEAP versus placebo, with greater cornstarch reductions in both groups at Week 96.
2026-07-23 | Base editing for precision therapeutics.
Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.
2026-06-11 | Hepatocyte-specific Cas9-mediated editing of G6pc and Slc37a4 elicits comparable biochemical and regulatory responses between glycogen storage disease (GSD) type Ia and Ib mice.
Glycogen storage disease type I (GSD I) is an autosomal recessive inborn error of carbohydrate metabolism. Patients with GSD type Ia and Ib exhibit overlapping and distinct symptoms and complications. Notably, GSD Ia patients show more severe hypertriglyceridemia and higher risk of hepatic tumors than GSD Ib patients. Given the liver's pivotal role in these processes, this study utilized hepatocyte-specific CRISPR/Cas9-mediated somatic gene editing to explore the pathophysiological and biochemical adaptations in hepatic GSD Ia and Ib side-by-side. Additionally, hepatic histology, transcriptomics, and proteomics analysis was performed. Compared to controls, hepatic GSD Ia and Ib mice showed hepatomegaly, fasting hypoglycemia, hyperlactatemia, and increased uric acid in plasma, which was somewhat more pronounced in GSD Ia than Ib. Both GSD I subtypes showed similar reductions in hepatic acetyl-CoA precursor pool enrichment and increases in de novo biosynthesis of hepatic stearate and oleate. Interestingly, only GSD Ia mice showed mildly elevated plasma triglyceride and hepatic phosphate sugars. Metabolic changes were reflected at the transcriptomic and proteomic levels, with largely similar responses between GSD Ia and Ib livers. Moreover, altered mRNAs and protein levels related to nucleotide-binding oligomerization domain (NOD) signaling pathways, infection and inflammation, liver disease, and chemical carcinogenesis were somewhat more pronounced in hepatic GSD Ia than in GSD Ib mice. Overall, the metabolic disturbance was more severe in hepatocyte-specific GSD Ia than in GSD Ib mice, consistent with the clinical phenotype in patients. The metabolic disorders and specific metabolites, genes, and proteins identified in this study provided new insights into the pathophysiological and biochemical phenotypes of GSD I subtypes in the liver.
2026-02-12 | Trial Interviews to Explore Glycogen Storage Disease Type Ia Patient Experiences Following Gene Therapy
Background: Glycogen storage disease type Ia (GSDIa) is a rare, inherited, autosomal recessive deficiency of glucose-6-phosphatase (G6Pase), an enzyme necessary in glycogenolysis and gluconeogenesis. To maintain normal blood glucose levels and ensure survival, individuals living with GSDIa must frequently consume complex carbohydrates (eg, uncooked cornstarch). Dietary management can result in chronic complications and significant patient burden. DTX401 (pariglasgene brecaparvovec) is an investigational adeno-associated virus serotype 8 vector (AAV8)–based gene therapy designed to restore endogenous glucose production. Objectives: Patient experience interviews were conducted as part of an open-label, phase 1/2 dose-escalation trial (NCT03517085) evaluating the safety and efficacy of DTX401 in adults ≥18 years with GSDIa. Methods: Telephone interviews were conducted at Weeks 24, 52, and 104, using a semistructured interview guide. Qualitative interview data were audio recorded, transcribed, coded, and analyzed. Results: Most (86%; n = 6/7) reported overall symptom improvement and reduced burden following DTX401 treatment. Three (43%) reported no negative outcomes following gene therapy; 4 (57%) mentioned at least one negative change attributed to instances of blood sugar instability, lifestyle, or diet adjustments. Satisfaction fluctuated across timepoints; however, most were somewhat satisfied/very satisfied with gene therapy at Weeks 24 (80%), 52 (86%), and 104 (86%). No participants reported being very dissatisfied. Discussion: Following DTX401 treatment, most participants reported substantial reduction in cornstarch intake and corresponding improvements in symptoms, physical function, diet management, emotional function, self-perception, social function, sleep quality, work performance, and overall health. Few negative changes were reported. While some results regarding met expectations were mixed, most indicated they would still want gene therapy even if they had to continue cornstarch and if they had continued diet restrictions, and most reported satisfaction with treatment. While the study had limitations, interview results suggest that DTX401 helps to address aspects of the condition and treatment that patients have identified as burdensome. Conclusions: Most interviewees in this open-label trial of investigational DTX401 described positive experiences, including substantial reduction in burden and improved health-related quality of life following treatment throughout the trial. To optimize patient outcomes and experience with gene therapy, guidance on and close monitoring of dietary changes during implementation should be provided.
other
2026-09-23 | Rapid progression of β-cell dysfunction in a patient with glycogen storage disease type 1a complicated by diabetes: longitudinal assessment by serial OGTTs with a review of the literature.
Glycogen storage disease type 1a (GSD1a) is characterized by hypoglycemia in childhood; however, cases complicated by diabetes in adulthood have increasingly been reported. The clinical phenotype of GSD1a appears heterogeneous, and insulin secretory capacity in the patients has not been fully characterized. Herein, we report the case of a 20-year-old woman with GSD1a who was initially diagnosed with type 2 diabetes in early adulthood. The patient's glycemic control gradually deteriorated despite administration of oral antidiabetic agents. Longitudinal evaluation using 75-g oral glucose tolerance tests demonstrated a marked decline in insulin secretion within 10 months. Based on these findings, insulin therapy was initiated, resulting in stable glycemic control. This case suggests that rapid β-cell decompensation occurs during the clinical course of early-onset diabetes in young patients with GSD1a.
2023-05-25 | Glycogen Storage Disease Type I: Prognostic Factors and Treatment
Glycogen storage disease type I (GSD I) is an inherited disorder that hinders theability of the liver to effectively break down stored glycogen, leading to difficulties inmaintaining appropriate blood sugar levels. The main treatment for this aspect ofGSD I involves the use of filgrastim, although patients often require additionaltreatment for recurrent infections, and an enlarged spleen is a common side effect.Acute lactic acidosis, which can cause respiratory distress and ketoacidosis innewborns, can be triggered by minor illnesses and accompanied by severehypoglycemia. Early diagnosis and prompt initiation of appropriate metabolictreatment are crucial in preventing the devastating effects of this condition. Theoverall prognosis and long-term efficacy of treatment are influenced by variousfactors, including the timing of diagnosis, adherence to dietary protocols, andavailability of appropriate medical interventions.
2021-07-05 | The signaling pathways implicated in impairment of hepatic autophagy in glycogen storage disease type Ia.
Glucose-6-phosphatase-α (G6Pase-α or G6PC) deficiency in glycogen storage disease type-Ia (GSD-Ia) leads to impaired hepatic autophagy, a recycling process important for cellular metabolism and homeostasis. Autophagy can be regulated by several energy sensing pathways, including sirtuin 1 (SIRT1), forkhead box O (FoxO), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPAR-α), and mammalian target of rapamycin (mTOR). Using 10-day old global G6pc-deficient (G6pc-/-) mice, hepatic autophagy impairment was attributed to activation of mTOR and inhibition of AMPK signaling. In other studies, using adult liver-specific G6pc-deficient mice at both pre-tumor and tumor stages, hepatic autophagy impairment was attributed to downregulation of SIRT1 signaling and mTOR was not implicated. In this study, we provide a detailed analysis of the major autophagy pathways in young G6pc-/- mice over the first 4 weeks of life. We show that impaired SIRT1, FoxO3a, AMPK, and PPAR-α signaling are responsible for autophagy impairment but mTOR is involved minimally. Hepatic SIRT1 overexpression corrects defective autophagy, restores the expression of FoxO3a and liver kinase B1 but fails to normalize impaired PPAR-α expression or metabolic abnormalities associated with GSD-Ia. Importantly, restoration of hepatic G6Pase-α expression in G6pc-/- mice corrects defective autophagy, restores SIRT1/FoxO3a/AMPK/PPAR-α signaling and rectifies metabolic abnormalities. Taken together, these data show that hepatic autophagy impairment in GSD-Ia is mediated by downregulation of SIRT1/FoxO3a/AMPK/PPAR-α signaling.
2011-12-13 | Liver Glucokinase(A456V) Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase.
Recent reports point out the importance of the complex GK-GKRP in controlling glucose and lipid homeostasis. Several GK mutations affect GKRP binding, resulting in permanent activation of the enzyme. We hypothesize that hepatic overexpression of a mutated form of GK, GK A456V , described in a patient with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and could provide a model to study the consequences of GK-GKRP deregulation in vivo . GK A456V was overexpressed in the liver of streptozotocin diabetic mice. Metabolite profiling in serum and liver extracts, together with changes in key components of glucose and lipid homeostasis, were analyzed and compared to GK wild-type transfected livers. Cell compartmentalization of the mutant but not the wild-type GK was clearly affected in vivo, demonstrating impaired GKRP regulation. GK A456V overexpression markedly reduced blood glucose in the absence of dyslipidemia, in contrast to wild-type GK-overexpressing mice. Evidence in glucose utilization did not correlate with increased glycogen nor lactate levels in the liver. PEPCK mRNA was not affected, whereas the mRNA for the catalytic subunit of glucose-6-phosphatase was upregulated ~4 folds in the liver of GK A456V -treated animals, suggesting that glucose cycling was stimulated. Our results provide new insights into the complex GK regulatory network and validate liver-specific GK activation as a strategy for diabetes therapy.
2004-02-03 | A glucose-6-phosphate hydrolase, widely expressed outside the liver, can explain age-dependent resolution of hypoglycemia in glycogen storage disease type Ia.
A fine control of the blood glucose level is essential to avoid hyper- or hypo-glycemic shocks associated with many metabolic disorders, including diabetes mellitus and type I glycogen storage disease. Between meals, the primary source of blood glucose is gluconeogenesis and glycogenolysis. In the final step of both pathways, glucose-6-phosphate (G6P) is hydrolyzed to glucose by the glucose-6-phosphatase (G6Pase) complex. Because G6Pase (renamed G6Pase-alpha) is primarily expressed only in the liver, kidney, and intestine, it has implied that most other tissues cannot contribute to interprandial blood glucose homeostasis. We demonstrate that a novel, widely expressed G6Pase-related protein, PAP2.8/UGRP, renamed here G6Pase-beta, is an acid-labile, vanadate-sensitive, endoplasmic reticulum-associated phosphohydrolase, like G6Pase-alpha. Both enzymes have the same active site structure, exhibit a similar Km toward G6P, but the Vmax of G6Pase-alpha is approximately 6-fold greater than that of G6Pase-beta. Most importantly, G6Pase-beta couples with the G6P transporter to form an active G6Pase complex that can hydrolyze G6P to glucose. Our findings challenge the current dogma that only liver, kidney, and intestine can contribute to blood glucose homeostasis and explain why type Ia glycogen storage disease patients, lacking a functional liver/kidney/intestine G6Pase complex, are still capable of endogenous glucose production.
small molecules
2026-09-26 | Bempedoic Acid Treatment in Four Adult Patients with Glycogen Storage Disease Type 1a: A Retrospective, Exploratory Case Series
Background: Glycogen storage disease type 1a (GSD 1a) is an inborn error of metabolism due to glucose-6-phosphatase deficiency. Treatment consists of frequent, carbohydrate-rich meals, intake of glucose polymers like uncooked cornstarch, or drip feeding in small infants. Although dietary treatment is challenging, it has improved the long-term outcomes for patients with GSD 1a. Nevertheless, several complications, including dyslipidaemia, remain difficult to manage, and early atherosclerosis with risk for ischemic stroke is a potential long-term concern. We propose bempedoic acid (BA) as a potential treatment option for dyslipidaemia in adult patients with GSD 1a. BA is an approved lipid-lowering therapy and may have additional beneficial metabolic effects in patients with GSD 1a. We hypothesize that BA may reduce malonyl-CoA concentrations and thereby alleviate the inhibition of mitochondrial fatty acid oxidation. This could potentially contribute to improved metabolic stability in patients with GSD 1a. Methods: Four adult female patients with GSD 1a and dyslipidaemia received BA at a dose of 180 mg once daily for 2–5 years. In this retrospective case series, we explored potential additional effects of BA treatment beyond its established lipid-lowering effect. Results: Under BA treatment, patients reported prolonged fasting periods, and carbohydrate intake could be reduced in some patients. Plasma lactate concentrations decreased during treatment, while triglyceride concentrations decreased in two patients but increased in the others. Two patients experienced a slight, clinically irrelevant increase in serum uric acid concentrations, a known adverse effect of BA. No other adverse effects were observed. Conclusions: In this retrospective, uncontrolled, single-center case series, BA was associated not only with its expected lipid-lowering effect, but also with potential improvements in metabolic control and prolonged fasting tolerance in adults with GSD 1a. However, these preliminary observations require confirmation in larger, prospective, controlled studies. Future studies should include standardized metabolic assessments and direct measurements of key metabolites involved in the pathophysiology of GSD 1a. Preclinical studies using appropriate animal models may further contribute to elucidating the underlying mechanisms and potential metabolic effects of BA.
2026-09-15 | Generation of a glycogen storage disease mouse model with fatty liver and its treatment by PPAR-α agonist bezafibrate.
Fatty liver is considered the pathological basis for the development of glycogen storage disease type Ia (GSDIa); however, due to the lack of suitable animal models, the mechanism underlying fatty liver development in GSDIa is largely unknown. This study employed surrogate breastfeeding to enable the survival of glucose-6-phosphatase catalytic (G6PC) knockout (KO) mice into adulthood, and then analyzed fatty liver phenotypes in 3-month-old KO (KO-3), 6-month-old KO (KO-6), and 9-month-old KO (KO-9) mice. KO-6 and KO-9 mice exhibited typical fatty liver phenotypes, and upregulation of glucose-6-phosphate (G6P). Moreover, both Western blot and qRT-PCR analysis showed significant upregulation of ChREBP, SREBP1 and fatty acid synthesis enzymes. RNA-seq heat maps revealed that KO-6 and KO-9 mice exhibited similar expression patterns, distinct from those observed in the wild-type (WT) and KO-3 groups. GO and KEGG analysis further revealed changes in lipid metabolism pathways in KO-6 and KO-9 mice, as well as PI3K-Akt, AMPK, and MAPK signaling. Western blot analysis showed that the Akt and mTOR pathways were activated, while the AMPK pathway was downregulated, indicating impaired autophagy. Finally, bezafibrate, a proliferator-activated receptor α (PPAR-α) agonist, enhanced autophagic activity and attenuated inflammatory responses, fat deposition, and glycogen storage in G6PC KO mice. This study successfully generated a fatty liver model using G6PC KO adult mice and demonstrated that pharmacological activation of PPAR-α may have therapeutic potential in adult G6PC KO mice.
2026-09-02 | Continuous glucose monitoring–guided optimization of peritoneal dialysis prescription in glycogen storage disease type 1a: a case report
Abstract Background Glycogen storage disease type 1a (GSD-1a) is a rare inherited metabolic disorder characterized by impaired glucose homeostasis and progressive renal involvement. As life expectancy has improved, an increasing number of patients develop end-stage kidney disease (ESKD); however, optimal renal replacement therapy (RRT) strategies remain unclear. Case presentation We report a 48-year-old man with GSD-1a who progressed to ESKD and underwent initiation of peritoneal dialysis (PD). Despite dietary management, he experienced recurrent nocturnal hypoglycemia. Continuous glucose monitoring (CGM) was used to evaluate glucose profiles under different PD modalities. Intermittent PD without nocturnal dialysate dwelling and continuous ambulatory PD were insufficient to prevent nocturnal hypoglycemia. Switching to nightly intermittent PD enabled continuous nocturnal glucose absorption from dialysate exchanges, resulting in the resolution of nocturnal hypoglycemia without the need for late-night snacks. Conclusion This case demonstrates that CGM can be a useful tool not only for detecting asymptomatic hypoglycemia but also for individualizing PD prescription in patients with GSD-1a. Individualized RRT strategies based on metabolic characteristics may improve safety and quality of life in this rare population.
2026-03-20 | Infantile extreme hypertriglyceridemia diagnosed as glycogen storage disease type Ia: A case report.
Glycogen storage disease type Ia (GSD Ia) typically presents with fasting hypoglycemia and hyperlipidemia. Atypical infantile presentations can delay diagnosis. We report an infant with extreme hypertriglyceridemia ultimately diagnosed as GSD Ia. A 5-month-old girl presented with poor appetite, growth retardation, hepatomegaly, and extreme hypertriglyceridemia (72 mmol/L), hypercholesterolemia, elevated transaminases, hyperuricemia, and hyperlactatemia, but initial normal blood glucose. Initial differentials included familial hypertriglyceridemia, but metabolic screening was normal. Whole-exome sequencing confirmed GSD Ia with compound heterozygous G6PC mutations (c.648G>T and c.814G>T). Initial lipid-lowering (low-fat diet, fenofibrate, omega-3, plasma exchange) reduced triglyceride. Post-diagnosis, she received lactose-free formula with frequent feeds and nocturnal nutrition; uncooked cornstarch was introduced at 6 months, though adherence was initially poor. Metabolic control was unstable until age 2 due to poor adherence. After 24 months of structured cornstarch therapy, fasting glucose normalized (4.2-6.6 mmol/L), triglycerides decreased (1.8-6.7 mmol/L), and catch-up growth occurred (height Z-score from -3.9 to -2.2 by 36 months). GSD Ia should be considered in infantile extreme hypertriglyceridemia with growth retardation, even without classic hypoglycemia. Sustained metabolic control requires multidisciplinary strategies addressing both biochemical and adherence barriers.
2026-01-01 | Continuous Glucose Monitoring–Driven Personalization of Cornstarch Therapy in Glycogen Storage Disease: A Retrospective Analysis
PURPOSE: Hepatic glycogen storage diseases (GSD), including types Ia, Ib, and IXa, are rare inherited disorders characterized by impaired hepatic glucose homeostasis. In GSD Ia, deficiency of glucose-6-phosphatase results in recurrent hypoglycemia and metabolic disturbances. Uncooked cornstarch (UCCS) is the standard therapy due to its slow digestion and sustained glucose release; however, dosing requirements vary according to age, digestion rate, metabolic demand, and lifestyle. Despite the central role of UCCS in long-term management, real-world data describing extended continuous glucose monitoring (CGM) patterns in hepatic GSD are extremely limited, and objective evidence guiding individualized dose adjustment remains scarce. This study examined CGM profiles in patients with hepatic GSD receiving long-term UCCS therapy and assessed the clinical utility of CGM in guiding individualized dosing adjustments. MATERIALS AND METHODS: We performed a retrospective, multi-year analysis of CGM data from 32 patients with hepatic GSD treated with UCCS. CGM traces were processed using 15-minute resampling, constrained interpolation, and physiologic clipping (40-400 mg/dL). Data were segmented into non-overlapping, calendar-anchored 7- and 14-day windows (anchor at 00:00) and retained when coverage was ≥70%. Per window, we calculated time in range (TIR, 70-150 mg/dL), time below range (TBR, <70 mg/dL), time above range (≥150 mg/dL), coefficient of variation, nocturnal TBR (00:00-06:00), and hypoglycemia burden [area under the curve (AUC) <70 mg/dL]. RESULTS: During routine clinic follow-up, CGM-informed, patient-specific UCCS and dietary adjustments maintained high TIR and low glycemic variability. Growth parameters and liver enzyme levels remained within normal limits. Episodes of recurrent nocturnal hypoglycemia identified on CGM prompted targeted modifications of UCCS dosing. CONCLUSION: A CGM-guided approach facilitates personalized UCCS management in hepatic GSD. Systematic review of TIR, nocturnal TBR, and AUC <70 mg/dL, alongside growth and liver assessments, provides a practical framework for optimizing long-term metabolic stability.
cell therapies
2026-08-28 | Simultaneous Liver-Kidney Transplantation from a Deceased Donor for Glycogen Storage Disease Type Ia: A Case Report.
Glycogen storage disease type Ia (GSD Ia) is an indication for simultaneous liver-kidney transplantation (SLKT) due to multiple hepatocellular adenomas and chronic renal failure. In this report, we describe a deceased-donor SLKT in a patient with GSD Ia who presented with hypoglycemic attacks, progressive multiple hepatocellular adenomas, and chronic renal failure. The patient was diagnosed with hepatomegaly at the age of 1 year and 6 months, with a diagnosis of GSD Ia, and was started on a special diet. She had been aware of liver tumors since 24 years of age. At 29 years of age, she underwent left lateral segmentectomy and radiofrequency ablation for multiple liver tumors. She began to suffer from renal dysfunction around 39 years of age, and then at 40 years of age, she was diagnosed with chronic renal failure and therefore was started on hemodialysis. She began having recurrent hypoglycemic attacks after the introduction of dialysis. Due to repeated hypoglycemic attacks, multiple hepatocellular adenomas, and chronic renal failure, she was deemed eligible for SLKT and thus was registered for deceased-donor SLKT at 41 years of age. She underwent SLKT at 46 years of age. The liver graft weight was 1060 g, and the graft-to-recipient body weight ratio was 2.41. The kidney graft weight was 170 g. The weight of the excised liver was 2710 g. Although no malignant findings were observed in the excised liver, multiple hepatocellular adenomas were identified. She was able to urinate independently immediately after the SLKT and was able to discontinue dialysis immediately afterward. Immunosuppressive therapy was initiated with basiliximab, ciclosporin A, methylprednisolone, and mycophenolate mofetil (MMF). However, due to abdominal pain and liver dysfunction caused by MMF, she was switched to mizoribine on POD 46, and her abdominal pain improved thereafter. She progressed well and was discharged on POD 49. Her liver and kidney functions remained good approximately 2 years after the SLKT. Adult patients with GSD Ia require transplantation due to hypoglycemic attacks, multiple liver tumors, and chronic renal failure.
2025-08-30 | Liver Transplantation as a Metabolic Treatment in Glycogen Storage Disease Type Ia.
Glycogen storage disease type Ia (GSD Ia) is a rare autosomal recessive metabolic disorder characterized by glucose-6-phosphatase deficiency, leading to severe fasting hypoglycemia, hypertriglyceridemia, hyperuricemia, hepatic adenomas, and osteoporosis. While intensive dietary and pharmacologic therapy remains the cornerstone of treatment, a subset of patients fails to achieve metabolic control and develops life-altering complications. We report the case of a 20-year-old male with genetically confirmed GSD Ia who exhibited persistent hypoglycemia, severe hyperlipidemia, hepatic adenomas, and osteoporosis despite optimal medical management. Due to the progression of hepatic and systemic complications, the patient underwent living donor liver transplantation using his father as the donor. Posttransplant follow-up demonstrated complete resolution of metabolic abnormalities, including hypoglycemia and dyslipidemia, normalization of liver function tests, and significant improvement in bone mineral density and quality of life. This case highlights the role of liver transplantation as a definitive metabolic treatment in selected patients with GSD Ia, offering not only biochemical correction but also prevention of neoplastic transformation and reversal of skeletal complications.
2014-11-04 | Biodistribution of adult derived human liver stem cells following intraportal infusion in a 17-year-old patient with glycogenosis type 1A.
Current treatment of inherited liver inborn errors of metabolism in children consists in appropriate diet and drugs and, for unstable patients, final orthotopic liver transplantation. Unfortunately, liver transplantation remains not easily available because of organ shortage and imposes inherent risks and lifelong immunosuppressive therapy. Therefore alternative treatments are required. Hepatocytes transplantation and its limitations led to consider innovative alternative such as transplantation of adult derived human liver stem cells (ADLHSC). These cells present high proliferative capacity, good resistance to cryopreservation and ability to differentiate into hepatocyte-like cells displaying mature hepatocyte functions. Biodistribution of ADHLSC had never been assessed after infusion through the portal vein in patients. This information is required to determine the safety of the method. ADHLSC were efficiently labelled with 111-Indium DTPA radiotracer and SPECT imaging was used for the acquisition of whole body imaging to document short term biodistribution of ADHLSC. Following infusion through the portal vein, ADHLSC diffused homogenously throughout the liver and remained strictly within the targeted organ. Images were acquired until 5 days after infusion. At that time, no signal was observed in any other organs except the liver. Urinary excretion of 111-Indium DTPA was also monitored. For the first time, we documented the short term biodistribution of ADHLSC within the liver after infusion through the portal vein.
2014-08-28 | Lessons from new mouse models of glycogen storage disease type 1a in relation to the time course and organ specificity of the disease
Patients with glycogen storage diseases type 1 (GSD1) suffer from life-threatening hypoglycaemia, when left untreated. Despite an intensive dietary treatment, patients develop severe complications, such as liver tumors and renal failure, with aging. Until now, the animal models available for studying the GSD1 did not survive after weaning. To gain further insights into the molecular mechanisms of the disease and to evaluate potential treatment strategies, we have recently developed novel mouse models in which the catalytic subunit of glucose-6 phosphatase (G6pc) is deleted in each glucose-producing organ specifically. For that, B6.G6pc(ex3lox/ex3lox) mice were crossed with transgenic mice expressing a recombinase under the control of the serum albumin, the kidney androgen protein or the villin promoter, in order to obtain liver, kidney or intestine G6pc(-/-) mice, respectively. As opposed to total G6pc knockout mice, tissue-specific G6pc deficiency allows mice to maintain their blood glucose by inducing glucose production in the other gluconeogenic organs. Even though it is considered that glucose is produced mainly by the liver, liver G6pc(-/-) mice are perfectly viable and exhibit the same hepatic pathological features as GSD1 patients, including the late development of hepatocellular adenomas and carcinomas. Interestingly, renal G6pc(-/-) mice developed renal symptoms similar to the early human GSD1 nephropathy. This includes glycogen overload that leads to nephromegaly and morphological and functional alterations in the kidneys. Thus, our data suggest that renal G6Pase deficiency per se is sufficient to induce the renal pathology of GSD1. Therefore, these new mouse models should allow us to improve the strategies of treatment on both nutritional and pharmacological points of view.
2014-04-09 | Liver transplantation in glycogen storage disease type I
Glycogen storage disease type I (GSDI), an inborn error of carbohydrate metabolism, is caused by defects in the glucose-6-transporter/glucose-6-phosphatase complex, which is essential in glucose homeostasis. Two types exist, GSDIa and GSDIb, each caused by different defects in the complex. GSDIa is characterized by fasting intolerance and subsequent metabolic derangements. In addition to these clinical manifestations, patients with GSDIb suffer from neutropenia with neutrophil dysfunction and inflammatory bowel disease. With the feasibility of novel cell-based therapies, including hepatocyte transplantations and liver stem cell transplantations, it is essential to consider long term outcomes of liver replacement therapy. We reviewed all GSDI patients with liver transplantation identified in literature and through personal communication with treating physicians. Our review shows that all 80 GSDI patients showed improved metabolic control and normal fasting tolerance after liver transplantation. Although some complications might be caused by disease progression, most complications seemed related to the liver transplantation procedure and subsequent immune suppression. These results highlight the potential of other therapeutic strategies, like cell-based therapies for liver replacement, which are expected to normalize liver function with a lower risk of complications of the procedure and immune suppression.
oligonucleotides
2023-12-04 | A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T.
Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-α (G6Pase-α, encoded by G6PC), which is primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves life expectancy, patients still experience intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a but potentially require complicated glycemic management throughout life. Here, we present an oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. We generated a mouse strain with homozygous knockin of this variant that well reflected the pathophysiology of patients with GSD1a. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b had long-lasting efficacy of more than 12 weeks in mice that received a single dose and had favorable pharmacokinetics and tolerability in mice and monkeys. These findings together indicate that this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.
2019-06-26 | Inhibition of Glycogen Synthase II with RNAi Prevents Liver Injury in Mouse Models of Glycogen Storage Diseases.
Glycogen storage diseases (GSDs) of the liver are devastating disorders presenting with fasting hypoglycemia as well as hepatic glycogen and lipid accumulation, which could lead to long-term liver damage. Diet control is frequently utilized to manage the potentially dangerous hypoglycemia, but there is currently no effective pharmacological treatment for preventing hepatomegaly and concurrent liver metabolic abnormalities, which could lead to fibrosis, cirrhosis, and hepatocellular adenoma or carcinoma. In this study, we demonstrate that inhibition of glycogen synthesis using an RNAi approach to silence hepatic Gys2 expression effectively prevents glycogen synthesis, glycogen accumulation, hepatomegaly, fibrosis, and nodule development in a mouse model of GSD III. Mechanistically, reduction of accumulated abnormally structured glycogen prevents proliferation of hepatocytes and activation of myofibroblasts as well as infiltration of mononuclear cells. Additionally, we show that silencing Gys2 expression reduces hepatic steatosis in a mouse model of GSD type Ia, where we hypothesize that the reduction of glycogen also reduces the production of excess glucose-6-phosphate and its subsequent diversion to lipid synthesis. Our results support therapeutic silencing of GYS2 expression to prevent glycogen and lipid accumulation, which mediate initial signals that subsequently trigger cascades of long-term liver injury in GSDs.
2013-06-10 | Enhanced gene expression of systemically administered plasmid DNA in the liver with therapeutic ultrasound and microbubbles.
Ultrasound-mediated delivery (USMD) of novel therapeutic agents in the presence of microbubbles is a potentially safe and effective method for gene therapy offering many desired characteristics, such as low toxicity, potential for repeated treatment, and organ specificity. In this study, we tested the capability of USMD to improve gene expression in mice livers using glycogen storage disease Type Ia as a model disease under systemic administration of naked plasmid DNA. Image-guided therapeutic ultrasound was used in two studies to provide therapeutic ultrasound to mice livers. In the first study, involving wild-type mice, control animals received naked plasmid DNA (pG6Pase 150 μg) via the tail vein, followed by an infusion of microbubbles; the treated animals additionally received therapeutic ultrasound (1 MHz). Following the procedure, the animals were left to recover and were subsequently euthanized after 2 d and liver samples were extracted. Reverse transcription polymerase chain reaction (RT-PCR) assays were performed on the samples to quantify mRNA expression. In addition, Western blot assays of FLAG-tagged glucose-6-phosphatase (G6Pase) were performed to evaluate protein expression. Ultrasound-exposed animals showed a 4-fold increase in G6Pase RNA in the liver, in comparison with control animals. Furthermore, results from Western blot analysis demonstrated a 2-fold increased protein expression in ultrasound-exposed animals after two days ( p < 0.05). A second pilot study was performed with G6Pase knockout mice, and the animals were monitored for correction of hypoglycemia over a period of 3 weeks before tissue analysis. The RT-PCR assays of samples from these animals demonstrated increased G6Pase RNA in the liver following ultrasound treatment. These results demonstrate that USMD can increase gene expression of systemically injected naked pDNA in the liver and also provide insight into the development of realistic approaches that can be translated into clinical practice.
2012-10-04 | Acoustically accessible window determination for ultrasound mediated treatment of glycogen storage disease type Ia patients
Glycogen storage disease type Ia (GSDIa) is caused by an inherited single-gene defect resulting in an impaired glycogen to glucose conversion pathway. Targeted ultrasound mediated delivery (USMD) of plasmid DNA (pDNA) to liver in conjunction with microbubbles may provide a potential treatment for GSDIa patients. As the success of USMD treatments is largely dependent on the accessibility of the targeted tissue by the focused ultrasound beam, this study presents a quantitative approach to determine the acoustically accessible liver volume in GSDIa patients. Models of focused ultrasound beam profiles for transducers of varying aperture and focal lengths were applied to abdomen models reconstructed from suitable CT and MRI images. Transducer manipulations (simulating USMD treatment procedures) were implemented via transducer translations and rotations with the intent of targeting and exposing the entire liver to ultrasound. Results indicate that acoustically accessible liver volumes can be as large as 50% of the entire liver volume for GSDIa patients and on average 3 times larger compared to a healthy adult group due to GSDIa patients' increased liver size. Detailed descriptions of the evaluation algorithm, transducer-and abdomen models are presented, together with implications for USMD treatments of GSDIa patients and transducer designs for USMD applications.
2011-07-24 | Acoustic Accessibility Investigation for Ultrasound Mediated Treatment of Glycogen Storage Disease Type Ia Patients
Glycogen storage disease type Ia (GSDIa) is caused by an inherited defect in the glucose-6-phosphatase gene. The recent advent of targeted ultrasound-mediated delivery (USMD) of plasmid DNA (pDNA) to the liver in conjunction with microbubbles may provide an alternative treatment option. This study focuses on determining the acoustically accessible liver volume in GSDIa patients using transducer models of various geometries with an image-based geometry-driven approach. Results show that transducers with longer focal lengths and smaller apertures (up to an f/number of 2) are able to access larger liver volumes in GSDIa patients while still being capable of delivering the required ultrasound dose in situ (2.5 MPa peak negative pressure at the focus). With sufficiently large acoustic windows and the ability to use glucose to easily assess efficacy, GSD appears to be a good model for testing USMD as proof of principle as a potential therapy for liver applications in general.
gene therapies
2026-09-08 | Genome Editing for Glycogen Storage Diseases.
Gene therapy has been developed for several glycogen storage diseases and has advanced into clinical trials. However, the limitations of these gene therapies with regard to stability following treatment early in life have led to the development of genome editing. Early results for genome editing in both glycogen storage disease type Ia and Pompe disease have demonstrated promising efficacy, and proof-of-concept studies as well as a clinical trial are underway. These studies will determine whether genome editing fulfills its promise with regard to stably treating glycogen storage diseases early in life.
2026-08-31 | Phase 3 Randomized Trial Results of DTX401 AAV Gene Therapy for the Treatment of GSDIa.
Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening inherited carbohydrate metabolism disorder caused by biallelic pathogenic G6PC gene variants resulting in deficiency of glucose-6-phosphatase. DTX401 is an investigational AAV8 vector containing the human G6PC gene. DTX401-CL301 is a pivotal, phase 3, double-blind, randomized, placebo-controlled trial of DTX401 in patients ≥ 8 years with GSDIa. The primary endpoint was percent change from Baseline to Week 48 in daily cornstarch intake for the DTX401 versus placebo group. Participants were randomly assigned (1:1) to blinded DTX401 or placebo. After the 48-week Primary Efficacy Analysis Period (PEAP), participants crossed over in a blinded manner for an additional 48-week blinded Crossover Period. Following randomization: 21 participants received DTX401; 25 received placebo. At Week 48, DTX401 treatment resulted in a statistically significant least squares (LS) mean (SE) daily cornstarch intake reduction of 41% (4.6) versus 10% (4.1) for Placebo (p < 0.0001). Clinical meaningfulness was evidenced by a mean desired percent reduction in daily cornstarch intake among those reporting in Baseline interviews (n = 33) of 45% (median = 41%). Greater and faster reductions in cornstarch were observed at Week 96 for the Crossover DTX401 group compared with the DTX401 group in the PEAP. The DTX401 safety profile was acceptable, and expected hepatic reactions consisting of transaminase elevations were managed with prophylactic corticosteroids. Treatment with DTX401 resulted in both a statistically significant and clinically meaningful reduction in cornstarch intake in the 48-week PEAP versus placebo, with greater cornstarch reductions in both groups at Week 96.
2026-07-23 | Base editing for precision therapeutics.
Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.
2026-06-11 | Hepatocyte-specific Cas9-mediated editing of G6pc and Slc37a4 elicits comparable biochemical and regulatory responses between glycogen storage disease (GSD) type Ia and Ib mice.
Glycogen storage disease type I (GSD I) is an autosomal recessive inborn error of carbohydrate metabolism. Patients with GSD type Ia and Ib exhibit overlapping and distinct symptoms and complications. Notably, GSD Ia patients show more severe hypertriglyceridemia and higher risk of hepatic tumors than GSD Ib patients. Given the liver's pivotal role in these processes, this study utilized hepatocyte-specific CRISPR/Cas9-mediated somatic gene editing to explore the pathophysiological and biochemical adaptations in hepatic GSD Ia and Ib side-by-side. Additionally, hepatic histology, transcriptomics, and proteomics analysis was performed. Compared to controls, hepatic GSD Ia and Ib mice showed hepatomegaly, fasting hypoglycemia, hyperlactatemia, and increased uric acid in plasma, which was somewhat more pronounced in GSD Ia than Ib. Both GSD I subtypes showed similar reductions in hepatic acetyl-CoA precursor pool enrichment and increases in de novo biosynthesis of hepatic stearate and oleate. Interestingly, only GSD Ia mice showed mildly elevated plasma triglyceride and hepatic phosphate sugars. Metabolic changes were reflected at the transcriptomic and proteomic levels, with largely similar responses between GSD Ia and Ib livers. Moreover, altered mRNAs and protein levels related to nucleotide-binding oligomerization domain (NOD) signaling pathways, infection and inflammation, liver disease, and chemical carcinogenesis were somewhat more pronounced in hepatic GSD Ia than in GSD Ib mice. Overall, the metabolic disturbance was more severe in hepatocyte-specific GSD Ia than in GSD Ib mice, consistent with the clinical phenotype in patients. The metabolic disorders and specific metabolites, genes, and proteins identified in this study provided new insights into the pathophysiological and biochemical phenotypes of GSD I subtypes in the liver.
2026-02-12 | Trial Interviews to Explore Glycogen Storage Disease Type Ia Patient Experiences Following Gene Therapy
Background: Glycogen storage disease type Ia (GSDIa) is a rare, inherited, autosomal recessive deficiency of glucose-6-phosphatase (G6Pase), an enzyme necessary in glycogenolysis and gluconeogenesis. To maintain normal blood glucose levels and ensure survival, individuals living with GSDIa must frequently consume complex carbohydrates (eg, uncooked cornstarch). Dietary management can result in chronic complications and significant patient burden. DTX401 (pariglasgene brecaparvovec) is an investigational adeno-associated virus serotype 8 vector (AAV8)–based gene therapy designed to restore endogenous glucose production. Objectives: Patient experience interviews were conducted as part of an open-label, phase 1/2 dose-escalation trial (NCT03517085) evaluating the safety and efficacy of DTX401 in adults ≥18 years with GSDIa. Methods: Telephone interviews were conducted at Weeks 24, 52, and 104, using a semistructured interview guide. Qualitative interview data were audio recorded, transcribed, coded, and analyzed. Results: Most (86%; n = 6/7) reported overall symptom improvement and reduced burden following DTX401 treatment. Three (43%) reported no negative outcomes following gene therapy; 4 (57%) mentioned at least one negative change attributed to instances of blood sugar instability, lifestyle, or diet adjustments. Satisfaction fluctuated across timepoints; however, most were somewhat satisfied/very satisfied with gene therapy at Weeks 24 (80%), 52 (86%), and 104 (86%). No participants reported being very dissatisfied. Discussion: Following DTX401 treatment, most participants reported substantial reduction in cornstarch intake and corresponding improvements in symptoms, physical function, diet management, emotional function, self-perception, social function, sleep quality, work performance, and overall health. Few negative changes were reported. While some results regarding met expectations were mixed, most indicated they would still want gene therapy even if they had to continue cornstarch and if they had continued diet restrictions, and most reported satisfaction with treatment. While the study had limitations, interview results suggest that DTX401 helps to address aspects of the condition and treatment that patients have identified as burdensome. Conclusions: Most interviewees in this open-label trial of investigational DTX401 described positive experiences, including substantial reduction in burden and improved health-related quality of life following treatment throughout the trial. To optimize patient outcomes and experience with gene therapy, guidance on and close monitoring of dietary changes during implementation should be provided.
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2026-09-23 | Rapid progression of β-cell dysfunction in a patient with glycogen storage disease type 1a complicated by diabetes: longitudinal assessment by serial OGTTs with a review of the literature.
Glycogen storage disease type 1a (GSD1a) is characterized by hypoglycemia in childhood; however, cases complicated by diabetes in adulthood have increasingly been reported. The clinical phenotype of GSD1a appears heterogeneous, and insulin secretory capacity in the patients has not been fully characterized. Herein, we report the case of a 20-year-old woman with GSD1a who was initially diagnosed with type 2 diabetes in early adulthood. The patient's glycemic control gradually deteriorated despite administration of oral antidiabetic agents. Longitudinal evaluation using 75-g oral glucose tolerance tests demonstrated a marked decline in insulin secretion within 10 months. Based on these findings, insulin therapy was initiated, resulting in stable glycemic control. This case suggests that rapid β-cell decompensation occurs during the clinical course of early-onset diabetes in young patients with GSD1a.
2023-05-25 | Glycogen Storage Disease Type I: Prognostic Factors and Treatment
Glycogen storage disease type I (GSD I) is an inherited disorder that hinders theability of the liver to effectively break down stored glycogen, leading to difficulties inmaintaining appropriate blood sugar levels. The main treatment for this aspect ofGSD I involves the use of filgrastim, although patients often require additionaltreatment for recurrent infections, and an enlarged spleen is a common side effect.Acute lactic acidosis, which can cause respiratory distress and ketoacidosis innewborns, can be triggered by minor illnesses and accompanied by severehypoglycemia. Early diagnosis and prompt initiation of appropriate metabolictreatment are crucial in preventing the devastating effects of this condition. Theoverall prognosis and long-term efficacy of treatment are influenced by variousfactors, including the timing of diagnosis, adherence to dietary protocols, andavailability of appropriate medical interventions.
2021-07-05 | The signaling pathways implicated in impairment of hepatic autophagy in glycogen storage disease type Ia.
Glucose-6-phosphatase-α (G6Pase-α or G6PC) deficiency in glycogen storage disease type-Ia (GSD-Ia) leads to impaired hepatic autophagy, a recycling process important for cellular metabolism and homeostasis. Autophagy can be regulated by several energy sensing pathways, including sirtuin 1 (SIRT1), forkhead box O (FoxO), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPAR-α), and mammalian target of rapamycin (mTOR). Using 10-day old global G6pc-deficient (G6pc-/-) mice, hepatic autophagy impairment was attributed to activation of mTOR and inhibition of AMPK signaling. In other studies, using adult liver-specific G6pc-deficient mice at both pre-tumor and tumor stages, hepatic autophagy impairment was attributed to downregulation of SIRT1 signaling and mTOR was not implicated. In this study, we provide a detailed analysis of the major autophagy pathways in young G6pc-/- mice over the first 4 weeks of life. We show that impaired SIRT1, FoxO3a, AMPK, and PPAR-α signaling are responsible for autophagy impairment but mTOR is involved minimally. Hepatic SIRT1 overexpression corrects defective autophagy, restores the expression of FoxO3a and liver kinase B1 but fails to normalize impaired PPAR-α expression or metabolic abnormalities associated with GSD-Ia. Importantly, restoration of hepatic G6Pase-α expression in G6pc-/- mice corrects defective autophagy, restores SIRT1/FoxO3a/AMPK/PPAR-α signaling and rectifies metabolic abnormalities. Taken together, these data show that hepatic autophagy impairment in GSD-Ia is mediated by downregulation of SIRT1/FoxO3a/AMPK/PPAR-α signaling.
2011-12-13 | Liver Glucokinase(A456V) Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase.
Recent reports point out the importance of the complex GK-GKRP in controlling glucose and lipid homeostasis. Several GK mutations affect GKRP binding, resulting in permanent activation of the enzyme. We hypothesize that hepatic overexpression of a mutated form of GK, GK A456V , described in a patient with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and could provide a model to study the consequences of GK-GKRP deregulation in vivo . GK A456V was overexpressed in the liver of streptozotocin diabetic mice. Metabolite profiling in serum and liver extracts, together with changes in key components of glucose and lipid homeostasis, were analyzed and compared to GK wild-type transfected livers. Cell compartmentalization of the mutant but not the wild-type GK was clearly affected in vivo, demonstrating impaired GKRP regulation. GK A456V overexpression markedly reduced blood glucose in the absence of dyslipidemia, in contrast to wild-type GK-overexpressing mice. Evidence in glucose utilization did not correlate with increased glycogen nor lactate levels in the liver. PEPCK mRNA was not affected, whereas the mRNA for the catalytic subunit of glucose-6-phosphatase was upregulated ~4 folds in the liver of GK A456V -treated animals, suggesting that glucose cycling was stimulated. Our results provide new insights into the complex GK regulatory network and validate liver-specific GK activation as a strategy for diabetes therapy.
2004-02-03 | A glucose-6-phosphate hydrolase, widely expressed outside the liver, can explain age-dependent resolution of hypoglycemia in glycogen storage disease type Ia.
A fine control of the blood glucose level is essential to avoid hyper- or hypo-glycemic shocks associated with many metabolic disorders, including diabetes mellitus and type I glycogen storage disease. Between meals, the primary source of blood glucose is gluconeogenesis and glycogenolysis. In the final step of both pathways, glucose-6-phosphate (G6P) is hydrolyzed to glucose by the glucose-6-phosphatase (G6Pase) complex. Because G6Pase (renamed G6Pase-alpha) is primarily expressed only in the liver, kidney, and intestine, it has implied that most other tissues cannot contribute to interprandial blood glucose homeostasis. We demonstrate that a novel, widely expressed G6Pase-related protein, PAP2.8/UGRP, renamed here G6Pase-beta, is an acid-labile, vanadate-sensitive, endoplasmic reticulum-associated phosphohydrolase, like G6Pase-alpha. Both enzymes have the same active site structure, exhibit a similar Km toward G6P, but the Vmax of G6Pase-alpha is approximately 6-fold greater than that of G6Pase-beta. Most importantly, G6Pase-beta couples with the G6P transporter to form an active G6Pase complex that can hydrolyze G6P to glucose. Our findings challenge the current dogma that only liver, kidney, and intestine can contribute to blood glucose homeostasis and explain why type Ia glycogen storage disease patients, lacking a functional liver/kidney/intestine G6Pase complex, are still capable of endogenous glucose production.
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Drug Discovery Landscape
5 orphan drug designations for Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia.
5 orphan drug designations for Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
mRNA encoding human glucose-6-phosphatase variant S298C | RNAs | EMA | Moderna Biotech Spain S.L. | |
Modified mRNA that encodes human glucose-6-phosphatase-alpha | RNAs | FDA | ModernaTX, Inc. | |
Adeno-associated viral vector serotype 8 containing the human glucose-6-phosphatase gene | gene therapies | EMA | Ultragenyx Germany GmbH | |
amylopectin | gene therapies | FDA | — | Voltera Pharmaceuticals, LLC |
AAV-G6Pase vector | gene therapies | FDA | GlyGenix Therapeutics, Inc. |
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