title: Helper-dependent canine adenovirus vector-mediated transgene expression in a neurodegenerative lysosomal storage disorder.
abstract: Mucopolysaccharidosis type IIIA (MPS-IIIA) is a severe neurodegenerative lysosomal storage disorder caused by a deficiency of N-sulfoglucosamine sulfohydrolase (SGSH) activity with subsequent accumulation of partially-degraded heparan sulfate and other glycolipids. In this study, we have evaluated a gene therapy approach using a helper-dependent canine adenovirus vector that expresses human SGSH as a means of delivering sustained transgene expression to the brain. Initial testing in a mixed neural cell culture model demonstrated that the vector could significantly increase SGSH activity in transduced cells, resulting in near-normalization of heparan sulfate-derived fragments. While administration of vector by direct injection into the brain of adult MPS-IIIA mice enabled transgene expression for at least 8.5 months post-treatment, it was only in discrete areas of brain. Heparan sulfate storage was reduced in some regions following treatment, however there was no improvement in secondary neuropathological changes. These data demonstrate that helper-dependent canine adenovirus vectors are capable of neural transduction and mediate long-term transgene expression, but increased SGSH expression throughout the brain is likely to be required in order to effectively treat all aspects of the MPS-IIIA phenotype.
authors.affiliation: Lysosomal Diseases Research Unit, SA Pathology at the Women's and Children's Hospital, Australia. adeline.lau@adelaide.edu.au
authors.forename: Adeline A
authors.initials: AA
authors.lastname: Lau
authors.forename: Tina
authors.initials: T
authors.lastname: Rozaklis
authors.forename: Sandy
authors.initials: S
authors.lastname: Ibanes
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Luck
authors.forename: Helen
authors.initials: H
authors.lastname: Beard
authors.forename: Sofia
authors.initials: S
authors.lastname: Hassiotis
authors.forename: Khalil
authors.initials: K
authors.lastname: Mazouni
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Kremer
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hemsley
mesh_terms: D006516:Adenoviruses, Canine / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006378:Helper Viruses / Q000235:genetics; D006867:Hydrolases / Q000235:genetics*; D009084:Mucopolysaccharidosis III / Q000628:therapy*; D019076:Transgenes
chemical_list: D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase