title: Neural stem cell gene therapy ameliorates pathology and function in a mouse model of globoid cell leukodystrophy.
abstract: Murine neural stem cells (mNSCs), either naive or genetically modified to express supranormal levels of β-galactocerebrosidase (GALC), were transplanted into the brain of Twitcher mice, a murine model of globoid cell leukodystrophy, a severe sphingolipidosis. Cells engrafted long-term into the host cytoarchitecture, producing functional GALC. Levels of enzyme activity in brain and spinal cord tissues were enhanced when GALC-overexpressing NSC were used. Enzymatic correction correlated with reduced tissue storage, decreased activation of astroglia and microglia, delayed onset of symptoms, and longer lifespan. Mechanisms underlying the therapeutic effect of mNSC included widespread enzyme distribution, cross-correction of host cells, anti-inflammatory activity, and neuroprotection. Similar cell engraftment and metabolic correction were reproduced using human NSC. Thus, NSC gene therapy rapidly reconstitutes sustained and long-lasting enzyme activity in central nervous system tissues. Combining this approach with treatments targeting the systemic disease associated with leukodystrophies may provide significant therapeutic benefit.
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Telethon Institute for Gene Therapy (HSR-TIGET), Milano, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Neri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ricca
authors.forename: Ilaria
authors.initials: I
authors.lastname: di Girolamo
authors.forename: Beatriz
authors.initials: B
authors.lastname: Alcala'-Franco
authors.forename: Chiara
authors.initials: C
authors.lastname: Cavazzin
authors.forename: Aldo
authors.initials: A
authors.lastname: Orlacchio
authors.forename: Sabata
authors.initials: S
authors.lastname: Martino
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Angela
authors.initials: A
authors.lastname: Gritti
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005698:Galactosylceramidase / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology; D033581:Stem Cell Transplantation; D019076:Transgenes
chemical_list: D005698:Galactosylceramidase