Open AccessNeural Stem Cell Gene Therapy Ameliorates Pathology and Function in a Mouse Model of Globoid Cell Leukodystrophy
Author(s) -
Neri Margherita,
Ricca Alessandra,
di Girolamo Ilaria,
Alcala'Franco Beatriz,
Cavazzin Chiara,
Orlacchio Aldo,
Martino Sabata,
Naldini Luigi,
Gritti Angela
Publication year - 2011
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.701
Subject(s) - leukodystrophy , biology , krabbe disease , neural stem cell , microglia , central nervous system , stem cell , genetic enhancement , cell therapy , neuroprotection , immunology , cell , microbiology and biotechnology , pathology , neuroscience , inflammation , disease , gene , biochemistry , medicine
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. S TEM C ELLS 2011;29:1559–1571