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

Mol Ther. 2018 Mar 7;26(3):890-901. doi: 10.1016/j.ymthe.2017.12.019. Epub 2017 Dec 28.


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.

Keywords: Cori disease; acid-alpha-glucosidase; adeno-associated vector; dual AAV vectors; gene therapy; glycogen storage disease type III; glycogenosis; neuromuscular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Blood Glucose
  • Dependovirus / genetics
  • Disease Models, Animal
  • Enzyme Activation
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Therapy* / methods
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Glycogen / metabolism
  • Glycogen Debranching Enzyme System / genetics*
  • Glycogen Debranching Enzyme System / metabolism
  • Glycogen Storage Disease Type III / diagnosis
  • Glycogen Storage Disease Type III / genetics*
  • Glycogen Storage Disease Type III / metabolism*
  • Glycogen Storage Disease Type III / therapy
  • Hepatocytes / metabolism
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Organ Specificity
  • Phenotype*


  • Biomarkers
  • Blood Glucose
  • Glycogen Debranching Enzyme System
  • Glycogen