{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:25:43Z","timestamp":1792074343996,"version":"4.4.0"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":1874,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Allogeneic fetal-derived human neural stem cells (hfNSCs) that are under clinical evaluation for several neurodegenerative diseases display a favorable safety profile, but require immunosuppression upon transplantation in patients. Neural progenitors derived from patient-specific induced pluripotent stem cells (iPSCs) may be relevant for autologous ex vivo gene-therapy applications to treat genetic diseases with unmet medical need. In this scenario, obtaining iPSC-derived neural stem cells (NSCs) showing a reliable \u201cNSC signature\u201d is mandatory. Here, we generated human iPSC (hiPSC) clones via reprogramming of skin fibroblasts derived from normal donors and patients affected by metachromatic leukodystrophy (MLD), a fatal neurodegenerative lysosomal storage disease caused by genetic defects of the arylsulfatase A (ARSA) enzyme. We differentiated hiPSCs into NSCs (hiPS-NSCs) sharing molecular, phenotypic, and functional identity with hfNSCs, which we used as a \u201cgold standard\u201d in a side-by-side comparison when validating the phenotype of hiPS-NSCs and predicting their performance after intracerebral transplantation. Using lentiviral vectors, we efficiently transduced MLD hiPSCs, achieving supraphysiological ARSA activity that further increased upon neural differentiation. Intracerebral transplantation of hiPS-NSCs into neonatal and adult immunodeficient MLD mice stably restored ARSA activity in the whole central nervous system. Importantly, we observed a significant decrease of sulfatide storage when ARSA-overexpressing cells were used, with a clear advantage in those mice receiving neonatal as compared with adult intervention. Thus, we generated a renewable source of ARSA-overexpressing iPSC-derived bona fide hNSCs with improved features compared with clinically approved hfNSCs. Patient-specific ARSA-overexpressing hiPS-NSCs may be used in autologous ex vivo gene therapy protocols to provide long-lasting enzymatic supply in MLD-affected brains.<\/jats:p>","DOI":"10.5966\/sctm.2015-0414","type":"journal-article","created":{"date-parts":[[2016,9,17]],"date-time":"2016-09-17T02:59:00Z","timestamp":1474081140000},"page":"352-368","source":"Crossref","is-referenced-by-count":73,"title":["Generation of Human Induced Pluripotent Stem Cell-Derived Bona Fide Neural Stem Cells for Ex Vivo Gene Therapy of Metachromatic Leukodystrophy"],"prefix":"10.1093","volume":"6","author":[{"given":"Vasco","family":"Meneghini","sequence":"first","affiliation":[{"name":"a San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Frati","sequence":"additional","affiliation":[{"name":"a San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Sala","sequence":"additional","affiliation":[{"name":"a San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"De Cicco","sequence":"additional","affiliation":[{"name":"a San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Luciani","sequence":"additional","affiliation":[{"name":"a San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cavazzin","sequence":"additional","affiliation":[{"name":"a San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Paulis","sequence":"additional","affiliation":[{"name":"b National Research Council, Milan, Italy"},{"name":"c Humanitas Clinical and Research Center, Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wieslawa","family":"Mentzen","sequence":"additional","affiliation":[{"name":"d BioFlag Ltd., Pula, Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Morena","sequence":"additional","affiliation":[{"name":"e Biochemistry and Molecular Biology Unit, Department of Chemistry, Biology and Biotechnologies, University of Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Giannelli","sequence":"additional","affiliation":[{"name":"f Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Sanvito","sequence":"additional","affiliation":[{"name":"g Anatomy and Histopathology Department, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Villa","sequence":"additional","affiliation":[{"name":"a San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"},{"name":"b National Research Council, Milan, Italy"},{"name":"c Humanitas Clinical and Research Center, Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bulfone","sequence":"additional","affiliation":[{"name":"d BioFlag Ltd., Pula, Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vania","family":"Broccoli","sequence":"additional","affiliation":[{"name":"f Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabata","family":"Martino","sequence":"additional","affiliation":[{"name":"e Biochemistry and Molecular Biology Unit, Department of Chemistry, Biology and Biotechnologies, University of Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Gritti","sequence":"additional","affiliation":[{"name":"a San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,9,16]]},"reference":[{"key":"2022022809300634400_R1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/nrn2761","article-title":"Neural stem cell systems: Physiological players or in vitro 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