Neural stem cell gene therapy ameliorates pathology and function in a mouse model of globoid cell leukodystrophy

Margherita Neri, Alessandra Ricca, Ilaria Di Girolamo, Beatriz Alcala'-Franco, Chiara Cavazzin, Aldo Orlacchio, Sabata Martino, Luigi Naldini, Angela Gritti

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1559-1571
Number of pages13
JournalStem Cells
Issue number10
Publication statusPublished - Oct 2011


  • Gene therapy
  • Leukodystrophies
  • Lysosomal storage diseases
  • Nervous system
  • Neural stem cells
  • Stem cell transplantation

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine


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