title: Sustained production of beta-glucuronidase from localized sites after AAV vector gene transfer results in widespread distribution of enzyme and reversal of lysosomal storage lesions in a large volume of brain in mucopolysaccharidosis VII mice.
abstract: The lysosomal storage disorders are a large group of inherited diseases that involve central nervous system degeneration. The disease in the brain has generally been refractory to treatment, which will require long-term correction of lesions dispersed throughout the central nervous system to be effective. A promising approach is somatic gene therapy but the methods have so far been inadequate because they have only achieved short-term or localized improvements. A potential approach to overcome these limitations is to obtain sustained high level expression and secretion of the missing normal enzyme from a small group of cells for export to neighboring diseased cells, which might allow the therapeutic protein to reach distal sites. We tested this in a mouse model of mucopolysaccharidosis VII (Sly disease) using an adeno-associated virus vector. After a single treatment the vector continuously produced the normal enzyme from infected cells at the injection sites. The secreted enzyme was disseminated along most of the neuraxis, resulting in widespread reversal of the hallmark pathology. An extensive sphere of correction surrounding the transduction sites was created, suggesting that a limited number of appropriately spaced sites of gene transfer may provide overlapping spheres of enzyme diffusion to cover a large volume of brain tissue.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Skorupa
authors.forename: K J
authors.initials: KJ
authors.lastname: Fisher
authors.forename: J M
authors.initials: JM
authors.lastname: Wilson
authors.forename: M K
authors.initials: MK
authors.lastname: Parente
authors.forename: J H
authors.initials: JH
authors.lastname: Wolfe
mesh_terms: D000818:Animals; D002540:Cerebral Cortex; D003342:Corpus Striatum; D000229:Dependovirus / Q000235:genetics*; D004058:Diffusion; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use*; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics; D006624:Hippocampus; D007267:Injections; D008247:Lysosomes / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D016538:Mucopolysaccharidosis VII / Q000473:pathology / Q000628:therapy*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D013788:Thalamus
chemical_list: D009419:Nerve Tissue Proteins; D005966:Glucuronidase