Journal
STEM CELLS
Volume 29, Issue 10, Pages 1559-1571Publisher
WILEY
DOI: 10.1002/stem.701
Keywords
Lysosomal storage diseases; Leukodystrophies; Nervous system; Neural stem cells; Gene therapy; Stem cell transplantation
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Funding
- Italian Telethon Foundation [TGT06B02]
- Italian Ministry of Health [56 L 289/2002]
- National Tay-Sachs and Allied Disease (NTSAD)
- ELA Foundation [ELA 2008-027I5]
- European Union [FP7/2007-2013, 241622]
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Murine neural stem cells (mNSCs), either naive or genetically modified to express supranormal levels of beta-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. STEM CELLS 2011;29:1559-1571
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