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The Journal of Neuroscience, March 22, 2006, 26(12):3109-3119; doi:10.1523/JNEUROSCI.4366-05.2006

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Neurobiology of Disease
Oligodendroglial Progenitor Cell Therapy Limits Central Neurological Deficits in Mice with Metachromatic Leukodystrophy

Maria I. Givogri,¹ Francesca Galbiati,¹ Stefania Fasano,^2,5 Stefano Amadio,³ Laura Perani,¹ Daniela Superchi,¹ Pablo Morana,³ Ubaldo Del Carro,³ Sergio Marchesini,⁴ Riccardo Brambilla,² Lawrence Wrabetz,² and Ernesto Bongarzone¹

¹Telethon Institute for Gene Therapy and Departments of ²Molecular Biology and Functional Genomics and ³Neurology, San Raffaele Scientific Institute, 20132 Milano, Italy, ⁴Department of Biomedical Science and Biotechnology, University of Brescia, 25123 Brescia, Italy and ⁵Institute of Psychology, School of Medicine, University of Milano, 20133 Milano, Italy

Correspondence should be addressed to either Dr. Maria I. Givogri or Dr. Ernesto R. Bongarzone, Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, Milano 20132, Italy. Email: givogri.maria{at}hsr.it or bongarzone.ernesto{at}hsr.it

This work describes the first successful oligodendrocyte-based cell therapy for presymptomatic arylsulfatase A (ARSA) null neonate mice, a murine model for human metachromatic leukodystrophy (MLD). We found that oligodendrocyte progenitors (OLPs) engrafted and survived into adulthood when transplanted in the neonatal MLD brain. Transplanted cells integrated nondisruptively, did not produce tumors, and survived as proteolipid protein- and MBP-positive postmitotic myelinating oligodendrocytes (OLs) intermingled with endogenous MLD OLs within the adult MLD white matter. Transplanted MLD mice had reduced sulfatide accumulation in the CNS, increased brain ARSA activity, and full prevention of the electrophysiological and motor deficits that characterize untreated MLD mice. Our results provide direct evidence that healthy OLPs can tolerate the neurotoxic accumulation of sulfatides that evolves during the postnatal development of the MLD brain and contribute to OL cell replacement to limit the accumulation of sulfatides and the evolution of CNS defects in this lysosomal storage disease mouse model.

Key words: myelin; oligodendrocytes; migration; transplantation; leukodystrophy; demyelination

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Received June 21, 2005; revised Feb. 4, 2006; accepted Feb. 5, 2006.

Correspondence should be addressed to either Dr. Maria I. Givogri or Dr. Ernesto R. Bongarzone, Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, Milano 20132, Italy. Email: givogri.maria{at}hsr.it or bongarzone.ernesto{at}hsr.it

This article has been cited by other articles:

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				S. A. Goldman, S. Schanz, and M. S. Windrem Stem cell-based strategies for treating pediatric disorders of myelin Hum. Mol. Genet., April 15, 2008; 17(R1): R76 - R83. [Abstract] [Full Text] [PDF]

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