title: Treatment of lysosomal storage disorders: cell therapy and gene therapy.
abstract: Most lysosomal storage diseases have central nervous system (CNS) involvement. No effective treatment is available at present. We investigated the usefulness of brain-directed gene therapy and cell therapy using mouse models of lysosomal storage diseases. For gene therapy to the CNS, a recombinant adenovirus encoding beta-galactocerebrosidase gene was injected into the cerebral ventricle of neonatal twitcher mice, a murine model of Krabbe disease. Improvements in neurological symptoms and a prolonged lifespan were observed. Brain activity of beta-galactocerebrosidase was increased significantly and the concentration of a cytotoxic metabolite, psychosine, was decreased. Pathological observations of the brain were also improved in treated twitcher mice. For cell therapy to the CNS, a neural stem cell line derived from human fetal brain was genetically engineered to overexpress beta-glucuronidase and transplanted into the cerebral ventricles of neonatal MPS VII mice, a model of beta-glucuronidase deficiency. Transplanted human neural stem cells were found to integrate and migrate in the host brain and to produce large amounts of beta-glucuronidase. Brain contents of the substrate of beta-glucuronidase were reduced and widespread clearing of lysosomal storage was observed in treated MPS VII mice. These data suggest that brain-directed gene/cell therapy may be useful in the treatment of neurological alterations in lysosomal storage diseases.
authors.affiliation: Department of Pediatrics, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan. yosh@sepia.ocn.ne.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Eto
authors.forename: J-S
authors.initials: JS
authors.lastname: Shen
authors.forename: X-L
authors.initials: XL
authors.lastname: Meng
authors.forename: T
authors.initials: T
authors.lastname: Ohashi
mesh_terms: D000818:Animals; D015316:Genetic Therapy; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000628:therapy*; D051379:Mice; D008818:Mice, Neurologic Mutants; D033581:Stem Cell Transplantation