title: Corrective GUSB transfer to the canine mucopolysaccharidosis VII brain.
abstract: Severe deficiency in lysosomal β-glucuronidase (β-glu) enzymatic activity results in mucopolysaccharidosis (MPS) VII, an orphan disease with symptoms often appearing in early childhood. Symptoms are variable, but many patients have multiple organ disorders including neurological defects. At the cellular level, deficiency in β-glu activity leads to abnormal accumulation of glycosaminoglycans (GAGs), and secondary accumulation of GM2 and GM3 gangliosides, which have been linked to neuroinflammation. There have been encouraging gene transfer studies in the MPS VII mouse brain, but this is the first study attempting the correction of the >200-fold larger and challenging canine MPS VII brain. Here, the efficacy of a helper-dependent (HD) canine adenovirus (CAV-2) vector harboring a human GUSB expression cassette (HD-RIGIE) in the MPS VII dog brain was tested. Vector genomes, β-glu activity, GAG content, lysosome morphology and neuropathology were analyzed and quantified. Our data demonstrated that CAV-2 vectors preferentially transduced neurons and axonal retrograde transport from the injection site to efferent regions was efficient. HD-RIGIE injections, associated with mild and transient immunosuppression, corrected neuropathology in injected and noninjected structures throughout the cerebrum. These data support the clinical evaluation of HD CAV-2 vectors to treat the neurological defects associated with MPS VII and possibly other neuropathic lysosomal storage diseases.
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Cubizolle
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Serratrice
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Skander
authors.affiliation: Institute National de la Recherche Agronomique, Ecole Nationale Veterinaire de Nantes, Nantes, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Colle
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Ibanes
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Gennetier
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Neus
authors.initials: N
authors.lastname: Bayo-Puxan
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Khalil
authors.initials: K
authors.lastname: Mazouni
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Mennechet
authors.affiliation: Institut de Recherche Thérapeutique, INSERM, Université de Nantes, Nantes, France.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Joussemet
authors.affiliation: Institute National de la Recherche Agronomique, Ecole Nationale Veterinaire de Nantes, Nantes, France.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cherel
authors.affiliation: Service de Neurochirurgie, Centre Hospitalier Universitaire Nord, Nantes, France.
authors.forename: Yaouen
authors.initials: Y
authors.lastname: Lajat
authors.affiliation: Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Vite
authors.affiliation: 1] Université de Montpellier I, Montpellier, France [2] Institut Régional du Cancer Montpellier, Montpellier, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Bernex
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Kalatzis
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
authors.affiliation: 1] Institut de Génétique Moléculaire de Montpellier, Montpellier, France [2] Université de Montpellier I, Montpellier, France [3] Université de Montpellier II, Montpellier, France.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Kremer
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D051379:Mice; D016538:Mucopolysaccharidosis VII / Q000235:genetics* / Q000628:therapy / Q000662:veterinary; D001617:beta-Glucosidase / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D006025:Glycosaminoglycans; D001617:beta-Glucosidase