title: GALC transduction leads to morphological improvement of the twitcher oligodendrocytes in vivo.
abstract: Globoid cell leukodystrophy (GLD, Krabbe disease) is a severe demyelinating disease caused by a genetic defect of beta-galactocerebrosidase (GALC). To date treatment to GLD is limited to hematopoietic stem cell transplantation. Experimental approaches by means of gene therapy in twitcher mouse, an authentic murine model of human GLD, showed significant but only marginal improvements of the disease. To clarify whether the introduction of GALC could provide beneficial effects on the oligodendrocytes in GLD, we transduced twitcher oligodendrocytes by stereotactically injecting recombinant retrovirus encoding GALC-myc-tag fusion gene into the forebrain subventricular zone of neonatal twitcher mouse. In vivo effects of exogenous GALC on twitcher oligodendrocytes were studied histologically by combined immunostaining for the myc-epitope and the oligodendroglial specific marker, pi form of glutathione-S-transferase, at around 40 days of age. We show here that GALC transduction led to dramatic morphological improvement of the twitcher oligodendrocytes comparing with those in untreated twitcher controls. This study provided direct in vivo evidence that GALC transduction could prevent or correct aberrant morphology of oligodendrocytes in GLD which may be closely related to the dysfunction and/or degeneration of oligodendrocytes and the demyelination in this disease.
authors.affiliation: Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Xing-Li
authors.initials: XL
authors.lastname: Meng
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Shen
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Watabe
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Eto
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000473:pathology / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics; D005698:Galactosylceramidase / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D016259:Genes, myc; D015316:Genetic Therapy / Q000379:methods*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009836:Oligodendroglia / Q000166:cytology* / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D000939:Epitopes; D005982:Glutathione Transferase; D005698:Galactosylceramidase