title: Central nervous system delivery of helper-dependent canine adenovirus corrects neuropathology and behavior in mucopolysaccharidosis type VII mice.
abstract: Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders because of their preferential transduction of neurons and efficient retrograde axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing β-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in β-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction. After intracranial administration of HD-RIGIE, we show long-term expression of β-glucuronidase that led to correction of neuropathology around the injection site and in distal areas. This phenotypic correction correlated with a decrease in secondary-elevated lysosomal enzyme activity and glycosaminoglycan levels, consistent with global biochemical correction. Moreover, HD-RIGIE-treated mice show significant cognitive improvement. Thus, injections of HD-CAV-2 vectors in the brain allow a global and sustained expression and may have implications for brain therapy in patients with lysosomal storage disease.
authors.affiliation: 1 Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Medicine, Universitat Autònoma de Barcelona , 08193 Bellaterra, Barcelona, Spain .
authors.forename: Lorena
authors.initials: L
authors.lastname: Ariza
authors.forename: Lydia
authors.initials: L
authors.lastname: Giménez-Llort
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cubizolle
authors.forename: Gemma
authors.initials: G
authors.lastname: Pagès
authors.forename: Belén
authors.initials: B
authors.lastname: García-Lareu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Serratrice
authors.forename: Dan
authors.initials: D
authors.lastname: Cots
authors.forename: Rosemary
authors.initials: R
authors.lastname: Thwaite
authors.forename: Miguel
authors.initials: M
authors.lastname: Chillón
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Kremer
authors.forename: Assumpció
authors.initials: A
authors.lastname: Bosch
mesh_terms: D006516:Adenoviruses, Canine / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D004789:Enzyme Activation; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006378:Helper Viruses; D007113:Immunity, Innate; D007267:Injections; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D017628:Microglia / Q000276:immunology; D016538:Mucopolysaccharidosis VII / Q000235:genetics* / Q000628:therapy*; D019076:Transgenes
chemical_list: D006025:Glycosaminoglycans; D005966:Glucuronidase