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

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

Author information

1
INTEGRARE, Genethon, Inserm, Univ Evry, Université Paris-Saclay, 91002 Evry, France; University Pierre and Marie Curie Paris 6 and INSERM U974, Paris, France.
2
Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
3
INTEGRARE, Genethon, Inserm, Univ Evry, Université Paris-Saclay, 91002 Evry, France; Genethon, 91002 Evry, France.
4
Université Lyon 1, Villeurbanne 69622, France.
5
University Pierre and Marie Curie Paris 6 and INSERM U974, Paris, France.
6
Genethon, 91002 Evry, France.
7
Myology Institute, Neuromuscular Morphology Unit, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Sorbonne Universités UPMC Univ Paris 06, 75005 Paris, France; Paris-Est neuromuscular center, Pitié-Salpêtrière Hospital, APHP, 75005 Paris, France; Raymond Poincaré Teaching Hospital, APHP, 92380 Garches, France.
8
Myology Institute, Neuromuscular Morphology Unit, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Sorbonne Universités UPMC Univ Paris 06, 75005 Paris, France.
9
Institut National de la Santé et de la Recherche Médicale, U1213, Lyon 69008, France; Université Lyon 1, Villeurbanne 69622, France.
10
INTEGRARE, Genethon, Inserm, Univ Evry, Université Paris-Saclay, 91002 Evry, France; Genethon, 91002 Evry, France. Electronic address: gronzitti@genethon.fr.
11
INTEGRARE, Genethon, Inserm, Univ Evry, Université Paris-Saclay, 91002 Evry, France; University Pierre and Marie Curie Paris 6 and INSERM U974, Paris, France; Genethon, 91002 Evry, France. Electronic address: fmingozzi@genethon.fr.

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.

KEYWORDS:

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

PMID:
29396266
PMCID:
PMC5910667
[Available on 2019-03-07]
DOI:
10.1016/j.ymthe.2017.12.019

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