Systemic Correction of Murine Glycogen Storage Disease Type IV by an AAV-Mediated Gene Therapy

Yi, Haiqing; Zhang, Quan; Brooks, Elizabeth D.; Yang, Chunyu; Thurberg, Beth L.; Kishnani, Priya S.; Sun, Baodong

doi:10.1089/hum.2016.099

Cited by 14 publications

(12 citation statements)

References 38 publications

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“…To conclude, this study demonstrates the potential of dietary management in a subset of GSD IV patients, as it should be considered in clinically stable patients prior to pursuing LT. This is particularly important as new treatments are being investigated for the hepatic glycogen storage diseases, including GSD IV, such as pharmacologic therapies, 32 gene therapy, 33 base editing, 34 RNA inhibition, 35 and mRNA therapy 36 …”

Section: Discussionmentioning

confidence: 99%

The potential of dietary treatment in patients with glycogen storage disease type IV

Derks

Peeks

Boer

et al. 2020

J of Inher Metab Disea

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There is paucity of literature on dietary treatment in glycogen storage disease (GSD) type IV and formal guidelines are not available. Traditionally, liver transplantation was considered the only treatment option for GSD IV. In light of the success of dietary treatment for the other hepatic forms of GSD, we have initiated this observational study to assess the outcomes of medical diets, which limit the accumulation of glycogen. Clinical, dietary, laboratory, and imaging data for 15 GSD IV patients from three centres are presented. Medical diets may have the potential to delay or prevent liver transplantation, improve growth and normalize serum aminotransferases. Individual care plans aim to avoid both hyperglycaemia, hypoglycaemia and/or hyperketosis, to minimize glycogen accumulation and catabolism, respectively. Multidisciplinary monitoring includes balancing between traditional markers of metabolic control (ie, growth, liver size, serum aminotransferases, glucose homeostasis, lactate, and ketones), liver function (ie, synthesis, bile flow and detoxification of protein), and symptoms and signs of portal hypertension.

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Section: Discussionmentioning

confidence: 99%

The potential of dietary treatment in patients with glycogen storage disease type IV

Derks

Peeks

Boer

et al. 2020

J of Inher Metab Disea

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show abstract

“…The findings of diffuse and dense PB accumulation in hepatic macrophages and their reduction in Gbe1 ys / ys Gys1 +/− mice highlight a relatively unexplored aspect of GSD IV pathology. Hypertrophic hepatic macrophages have been previously described in Gbe1 ys / ys murine liver, 29 and PBs have been commonly reported in hepatic and extra‐hepatic macrophages across GSD IV variants 30,31 . It remains unknown whether PBs in macrophages are consequent of endogenous glycogen metabolism and/or engulfment of exogenous PBs.…”

Section: Discussionmentioning

confidence: 99%

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

Chown

Wang

Zhao

et al. 2020

Ann Clin Transl Neurol

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Objective: Adult polyglucosan body disease (APBD) is an adult-onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. Methods: We characterized the effects of knocking out two proglycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. Results: APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro-and micro-gliosis in the brains of GYS1-and PPP1R3C-deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. Interpretation: GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.

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“…However, similar observations have been reported after the treatment of GSDIV mice with GAA that resulted in the clearance of liver, but not muscle, glycogen. 31 Based on the observation that overexpression of GAA alone does not fully correct GSDIII, we sought to address the enzymatic deficiency, hallmark of the disease, by directly restoring the GDE enzyme activity with AAV vectors. The fact that GDE is a large cytosolic protein of 175 kDa with two different enzymatic domains 32 complicates the design of AAV vectors expressing the enzyme, and it does not allow for the development of gene therapy strategies based on cross-correction.…”

Section: Discussionmentioning

confidence: 99%

Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression

et al. 2018

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Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by a deficiency of glycogen-debranching enzyme (GDE), which results in profound liver metabolism impairment and muscle weakness. To date, no cure is available for GSDIII and current treatments are mostly based on diet. Here we describe the development of a mouse model of GSDIII, which faithfully recapitulates the main features of the human condition. We used this model to develop and test novel therapies based on adeno-associated virus (AAV) vector-mediated gene transfer. First, we showed that overexpression of the lysosomal enzyme alpha-acid glucosidase (GAA) with an AAV vector led to a decrease in liver glycogen content but failed to reverse the disease phenotype. Using dual overlapping AAV vectors expressing the GDE transgene in muscle, we showed functional rescue with no impact on glucose metabolism. Liver expression of GDE, conversely, had a direct impact on blood glucose levels. These results provide proof of concept of correction of GSDIII with AAV vectors, and they indicate that restoration of the enzyme deficiency in muscle and liver is necessary to address both the metabolic and neuromuscular manifestations of the disease.

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Systemic Correction of Murine Glycogen Storage Disease Type IV by an AAV-Mediated Gene Therapy

Cited by 14 publications

References 38 publications

The potential of dietary treatment in patients with glycogen storage disease type IV

The potential of dietary treatment in patients with glycogen storage disease type IV

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression

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