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

Abstract

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.

• Authors: 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 Rajas, Giacomo Pietro Comi, Giuseppe Ronzitti, Federico Mingozzi
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 26 Issue 3 Pg. 890-901 (03 07 2018) ISSN: 1525-0024 [Electronic] United States
• PMID: 29396266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The American Society of Gene and Cell Therapy. All rights reserved.

Chemical References

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

Topics

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