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

Patrice Vidal, Serena Pagliarani, Pasqualina Colella, Helena Costa Verdera, Louisa Jauze, Monika Gjorgjieva, Francesco Puzzo, Solenne Marmier, Fanny Collaud, Marcelo Simon Sola, Severine Charles, Sabrina Lucchiari, Laetitia van Wittenberghe, Alban Vignaud, Bernard Gjata, Isabelle Richard, Pascal Laforet, Edoardo Malfatti, Gilles Mithieux, Fabienne RajasGiacomo Pietro Comi, Giuseppe Ronzitti, Federico Mingozzi

Research output: Contribution to journalArticlepeer-review


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. Ronzitti, Mingozzi, and colleagues provide the first proof of concept of gene therapy for glycogen storage disease type III. Two parallel therapeutic strategies, explored in detail, provide novel, clinically relevant, and mechanistic findings on both gene therapy and, potentially, enzyme replacement therapeutic strategies for GSDIII.

Original languageEnglish
Pages (from-to)890-901
Number of pages12
JournalMolecular Therapy
Issue number3
Publication statusPublished - Mar 7 2018


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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


Dive into the research topics of 'Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression'. Together they form a unique fingerprint.

Cite this