title: Safe, efficient, and reproducible gene therapy of the brain in the dog models of Sanfilippo and Hurler syndromes.
abstract: Recent trials in patients with neurodegenerative diseases documented the safety of gene therapy based on adeno-associated virus (AAV) vectors deposited into the brain. Inborn errors of the metabolism are the most frequent causes of neurodegeneration in pre-adulthood. In Sanfilippo syndrome, a lysosomal storage disease in which heparan sulfate oligosaccharides accumulate, the onset of clinical manifestation is before 5 years. Studies in the mouse model showed that gene therapy providing the missing enzyme α-N-acetyl-glucosaminidase to brain cells prevents neurodegeneration and improves behavior. We now document safety and efficacy in affected dogs. Animals received eight deposits of a serotype 5 AAV vector, including vector prepared in insect Sf9 cells. As shown previously in dogs with the closely related Hurler syndrome, immunosuppression was necessary to prevent neuroinflammation and elimination of transduced cells. In immunosuppressed dogs, vector was efficiently delivered throughout the brain, induced α-N-acetyl-glucosaminidase production, cleared stored compounds and storage lesions. The suitability of the procedure for clinical application was further assessed in Hurler dogs, providing information on reproducibility, tolerance, appropriate vector type and dosage, and optimal age for treatment in a total number of 25 treated dogs. Results strongly support projects of human trials aimed at assessing this treatment in Sanfilippo syndrome.
authors.affiliation: Department of Animal Science, Iowa State University, Ames, IA, USA.
authors.forename: N Matthew
authors.initials: NM
authors.lastname: Ellinwood
authors.forename: Jérôme
authors.initials: J
authors.lastname: Ausseil
authors.forename: Nathalie
authors.initials: N
authors.lastname: Desmaris
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bigou
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Jackie K
authors.initials: JK
authors.lastname: Jens
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Snella
authors.forename: Eman E A
authors.initials: EE
authors.lastname: Mohammed
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Thomson
authors.forename: Sylvie
authors.initials: S
authors.lastname: Raoul
authors.forename: Béatrice
authors.initials: B
authors.lastname: Joussemet
authors.forename: Françoise
authors.initials: F
authors.lastname: Roux
authors.forename: Yan
authors.initials: Y
authors.lastname: Chérel
authors.forename: Yaouen
authors.initials: Y
authors.lastname: Lajat
authors.forename: Monique
authors.initials: M
authors.lastname: Piraud
authors.forename: Rachid
authors.initials: R
authors.lastname: Benchaouir
authors.forename: Stephan
authors.initials: S
authors.lastname: Hermening
authors.forename: Harald
authors.initials: H
authors.lastname: Petry
authors.forename: Roseline
authors.initials: R
authors.lastname: Froissart
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.forename: Carine
authors.initials: C
authors.lastname: Ciron
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.forename: Jennifer
authors.initials: J
authors.lastname: Parkes
authors.forename: Karen L
authors.initials: KL
authors.lastname: Kline
authors.forename: Irène
authors.initials: I
authors.lastname: Maire
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Vanier
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Heard
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Colle
mesh_terms: D000118:Acetylglucosaminidase / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D008059:Mucopolysaccharidosis I / Q000628:therapy*; D009084:Mucopolysaccharidosis III / Q000628:therapy*; D016133:Polymerase Chain Reaction
chemical_list: C033079:alpha-N-acetyl-D-glucosaminidase; D000118:Acetylglucosaminidase