title: Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of alpha-glucosidase in Pompe disease.
abstract: BACKGROUND
  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. Even if enzyme replacement therapy (ERT) has already proven some efficacy, its results remain heterogeneous in skeletal muscle, especially in cross reactive immunological material (CRIM)-negative patients. We investigated for the first time the use of hematopoietic stem cell (HSC) gene therapy in a murine model of GSDII.
  
  
  METHODS
  Deficient HSC were transduced with a lentiviral vector expressing human GAA or enhanced green fluorescent protein (GFP) under the control of the retroviral MND promoter and transplanted into lethally irradiated GSDII mice. Animals were then subjected to an ERT protocol for 5 weeks and monitored for metabolic correction and GAA-induced immune reaction.
  
  
  RESULTS
  GAA was expressed as a correctly processed protein, allowing a complete enzymatic correction in transduced deficient cells without toxicity. Seventeen weeks after transplantation, a partial restoration of the GAA enzymatic activity was observed in bone marrow and peripheral blood cells of GSDII mice, allowing a significant glycogen clearance in skeletal muscle. ERT induced a robust antibody response in GFP-transplanted mice, whereas no immune reaction could be detected in GAA-transplanted mice.
  
  
  CONCLUSIONS
  Lentiviral vector-mediated HSC gene therapy leads to a partial metabolic correction and induces a tolerance to ERT in GSDII mice. This strategy could enhance the efficacy of ERT in CRIM-negative Pompe patients.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Douillard-Guilloux
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Richard
authors.forename: Lionel
authors.initials: L
authors.lastname: Batista
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillaud
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D057487:Enzyme Therapy; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006009:Glycogen Storage Disease Type II / Q000628:therapy*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000008:administration & dosage* / Q000235:genetics
chemical_list: D000520:alpha-Glucosidases