Abstract
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of arylsulfatase A (ARSA) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (PNS) and central nervous system (CNS), and early death of MLD patients. The ARSA knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the PNS and CNS. We showed that adeno-associated virus serotype 5-mediated gene transfer in the brain of ARSA knockout mice reverses Sulf storage and prevents neuropathological abnormalities and neuromotor disabilities when vector injections are performed at a pre-symptomatic stage of disease. Direct injection of viral particles into the brain of ARSA knockout mice at a symptomatic stage results in sustained expression of ARSA, prevention of Sulf storage and neuropathological abnormalities. Despite these significant corrections, the treated mice continue to develop neuromotor disability. We show that more subtle biochemical abnormalities involving gangliosides and galactocerebroside are in fact not corrected.
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Abbreviations
- AAV:
-
adeno-associated virus
- ARSA:
-
arylsulfatase A
- CNS:
-
central nervous system
- ELISA:
-
enzyme-linked immunosorbent assay
- ET:
-
early treated
- GalC:
-
galactosylceramide
- GALC:
-
galactocerebrosidase enzyme
- GFAP:
-
glial fibrillary acidic protein
- LSDs:
-
lysosomal storage diseases
- LT:
-
late treated
- MLD:
-
metachromatic leukodystrophy
- M6P:
-
mannose-6-phosphate
- PAS:
-
Periodic Acid Schiff
- PFA:
-
paraformaldehyde
- PNS:
-
peripheral nervous system
- Sulf:
-
sulfatide.
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Acknowledgements
We thank A Salvetti, P Moullier and the vector core of the Association Française contre les Myopathies in Nantes for the preparation of the AAV vector. We express our gratitude to R D'Hooge who contributed to the initial phase of this work. We also thank Frieda Franck (Antwerp, Belgium) for her excellent collaboration and J Lopez for her technical assistance. This work was supported by grants from the European Leukodystrophy Foundation (ELA), the National Organization for Rare Disorders (NORD), the Association Française contre les Myopathies (AFM), the GIS-Institut des maladies rares, the Fédération pour la Recherche sur le Cerveau, the Fondation pour la Recherche Médicale (FRM) and the Fund for Scientific Research-Flanders (FWO grant G.0038.05), agreement between the Institute Born-Bunge and the University of Antwerp, Neurosearch Antwerp, Antwerp Medical Research Foundation, the Thomas Riellaerts Fund. DVD holds a postdoctoral position at the University of Antwerp.
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Sevin, C., Verot, L., Benraiss, A. et al. Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer. Gene Ther 14, 405–414 (2007). https://doi.org/10.1038/sj.gt.3302883
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DOI: https://doi.org/10.1038/sj.gt.3302883
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