TY - JOUR
T1 - Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression
AU - Vidal, Patrice
AU - Pagliarani, Serena
AU - Colella, Pasqualina
AU - Costa Verdera, Helena
AU - Jauze, Louisa
AU - Gjorgjieva, Monika
AU - Puzzo, Francesco
AU - Marmier, Solenne
AU - Collaud, Fanny
AU - Simon Sola, Marcelo
AU - Charles, Severine
AU - Lucchiari, Sabrina
AU - van Wittenberghe, Laetitia
AU - Vignaud, Alban
AU - Gjata, Bernard
AU - Richard, Isabelle
AU - Laforet, Pascal
AU - Malfatti, Edoardo
AU - Mithieux, Gilles
AU - Rajas, Fabienne
AU - Comi, Giacomo Pietro
AU - Ronzitti, Giuseppe
AU - Mingozzi, Federico
PY - 2018/3/7
Y1 - 2018/3/7
N2 - 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.
AB - 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.
KW - acid-alpha-glucosidase
KW - adeno-associated vector
KW - Cori disease
KW - dual AAV vectors
KW - gene therapy
KW - glycogen storage disease type III
KW - glycogenosis
KW - neuromuscular disease
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UR - http://www.scopus.com/inward/citedby.url?scp=85041200925&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2017.12.019
DO - 10.1016/j.ymthe.2017.12.019
M3 - Article
AN - SCOPUS:85041200925
VL - 26
SP - 890
EP - 901
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 3
ER -