title: Central nervous system-directed AAV2/5-mediated gene therapy synergizes with bone marrow transplantation in the murine model of globoid-cell leukodystrophy.
abstract: Globoid-cell leukodystrophy (GLD) is a rapidly progressing inherited neurodegenerative disorder caused by a deficiency in galactosylceramidase activity. Previous studies in the murine model of GLD (Twitcher mouse) have shown that both bone marrow transplantation (BMT) and central nervous system (CNS)-directed gene therapy can be moderately effective at ameliorating certain aspects of GLD. As BMT and CNS-directed gene therapy target fundamentally different tissues, we tested the hypothesis that combining these disparate therapies would be more efficacious than either therapy alone. Mice receiving myeloreductive conditioning at birth followed by syngeneic BMT had approximately 25-35% donor chimerism. Untreated Twitcher mice, Twitcher mice treated with BMT alone, AAV2/5 alone, or a combination of BMT and AAV2/5 had mean lifespans of 39, 44, 49, and 104 days, respectively. Twitcher mice treated with a combination of BMT and AAV2/5 also had significantly improved performance in several behavioral tests and greater reduction in demyelination, astrocytosis, and macrophage infiltration compared to untreated Twitcher mice or mice that received either therapy alone. These data suggest that CNS-directed gene therapy synergizes with BMT. The combination of these disparate therapeutic approaches may form the basis for more effective treatment of this inherited neurodegenerative disorder.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
authors.forename: Darshong
authors.initials: D
authors.lastname: Lin
authors.forename: Anthony
authors.initials: A
authors.lastname: Donsante
authors.forename: Shannon
authors.initials: S
authors.lastname: Macauley
authors.forename: Beth
authors.initials: B
authors.lastname: Levy
authors.forename: Carole
authors.initials: C
authors.lastname: Vogler
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015415:Biomarkers; D001835:Body Weight; D016026:Bone Marrow Transplantation; D002490:Central Nervous System / Q000378:metabolism*; D046528:Chimerism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D015316:Genetic Therapy; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics* / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D008136:Longevity; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D014019:Tissue Donors; D019172:Transplantation Conditioning
chemical_list: D015415:Biomarkers