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: Y Eto, J-S Shen, X-L Meng, T Ohashi
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 27 Issue 3 Pg. 411-5 ( 2004) ISSN: 0141-8955 [Print] United States
• PMID: 15190197 (Publication Type: Journal Article, Review)

Topics

• Animals
• Genetic Therapy
• Humans
• Lysosomal Storage Diseases (therapy)
• Mice
• Mice, Neurologic Mutants
• Stem Cell Transplantation