title: Correction of glycogenosis type 2 by muscle-specific lentiviral vector.
abstract: Glycogen storage disease type II (GSDII) or Pompe disease is an inherited disease of glycogen metabolism caused by a lack of functional lysosomal acid alpha-glucosidase (GAA). Affected individuals store glycogen in lysosomes resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe form. We investigated for the first time the use of lentiviral vectors to correct the GSDII phenotype in human and murine GAA-deficient cells. Fibroblasts from infantile and adult GSDII patients were efficiently transduced by a GAA-expressing lentiviral vector placed under the control of the strong MND promoter, leading to a complete restoration of enzymatic activity. We also developed a muscle-specific lentiviral vector based on the synthetic C5-12 promoter and tested it on deficient myogenic satellite cells derived from a GSDII mouse model. GAA was expressed as a correctly processed protein allowing a complete enzymatic and metabolic correction in myoblasts and differentiated myotubes, as well as a significant mannose-6-phosphate (M6P)-dependent secretion reuptake by naive cells. Transduced cells showed lysosomal glycogen clearance, as demonstrated by electron microscopy. These results form the basis for a therapeutic approach of GSDII using lentiviral vector-mediated gene transfer into muscle stem cells.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U567, Paris, France. Emmanuel.Richard@u-bordeaux2.fr
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Richard
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Douillard-Guilloux
authors.forename: Lionel
authors.initials: L
authors.lastname: Batista
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillaud
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009132:Muscles / Q000378:metabolism*; D032446:Myoblasts / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D009928:Organ Specificity; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D014161:Transduction, Genetic; D038301:Virus Inactivation; D000520:alpha-Glucosidases / Q000235:genetics / Q000627:therapeutic use
chemical_list: D017527:Receptor, IGF Type 2; D006003:Glycogen; D000520:alpha-Glucosidases