title: Gene therapy of the brain in the dog model of Hurler's syndrome.
abstract: OBJECTIVE
  A defect of the lysosomal enzyme alpha-L-iduronidase (IDUA) interrupts the degradation of glycosaminoglycans in mucopolysaccharidosis type I, causing severe neurological manifestations in children with Hurler's syndrome. Delivery of the missing enzyme through stereotactic injection of adeno-associated virus vectors coding for IDUA prevents neuropathology in affected mice. We examined the efficacy and the safety of this approach in enzyme-deficient dogs.
  
  
  METHODS
  Because deficient dogs raise antibodies against IDUA in response to infusion, intracerebral vector injections were combined with an immunosuppressive regimen.
  
  
  RESULTS
  Treatment was tolerated well. We observed broad dispersion of vector genomes in the brain of efficiently immunosuppressed dogs. The delivery of IDUA to large areas, which could encompass the entire brain, prevented glycosaminoglycan and secondary ganglioside accumulations. This condition was associated with drastic reduction of neuropathology throughout the encephalon. In contrast, vector injection combined with partial immunosuppression was associated with subacute encephalitis, production of antibodies against IDUA in brain tissues, and elimination of genetically modified cells.
  
  
  CONCLUSIONS
  Gene therapy directed to the entire brain is feasible and may be beneficial to children with Hurler's syndrome. The possibility of subacute encephalitis emphasizes the importance of preventing immune response against IDUA, a problem that needs to be considered in similar therapies for other genetic defects.
authors.affiliation: Institut National de la Sante et de la Recherche Médicale U649, CHU Hôtel Dieu, Nantes, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Ciron
authors.forename: Nathalie
authors.initials: N
authors.lastname: Desmaris
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Colle
authors.forename: Sylvie
authors.initials: S
authors.lastname: Raoul
authors.forename: Béatrice
authors.initials: B
authors.lastname: Joussemet
authors.forename: Lucie
authors.initials: L
authors.lastname: Vérot
authors.forename: Jérôme
authors.initials: J
authors.lastname: Ausseil
authors.forename: Roseline
authors.initials: R
authors.lastname: Froissart
authors.forename: Françoise
authors.initials: F
authors.lastname: Roux
authors.forename: Yan
authors.initials: Y
authors.lastname: Chérel
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ferry
authors.forename: Yaouen
authors.initials: Y
authors.lastname: Lajat
authors.forename: Bertrand
authors.initials: B
authors.lastname: Schwartz
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Vanier
authors.forename: Irène
authors.initials: I
authors.lastname: Maire
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Heard
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000473:pathology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001835:Body Weight; D001921:Brain / Q000473:pathology*; D004285:Dogs; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006025:Glycosaminoglycans / Q000378:metabolism; D007068:Iduronidase / Q000276:immunology; D008297:Male; D008059:Mucopolysaccharidosis I / Q000473:pathology* / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013238:Stereotaxic Techniques
chemical_list: D001323:Autoantibodies; D005732:Gangliosides; D006025:Glycosaminoglycans; D007068:Iduronidase