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In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice

Abstract

Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.

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Figure 1: The MLD gene therapy model.
Figure 2: Intracranial vector administration and transduction of CNS cells.
Figure 3: Rescue of histopathology in MLD mice treated by ARSA gene transfer into the brain.
Figure 4: The therapeutic activity of ARSA gene transfer extends to the uninjected, contralateral side of the brain with longer time after treatment with ARSA vector.
Figure 5: Reconstitution of ARSA activity in the brains of MLD mice.
Figure 6: Long-term protection from learning impairment, neuronal damage and lipid storage in MLD mice treated by ARSA vector.

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Acknowledgements

We thank V. Gieselmann for providing the As2−/− founder mice and for discussions on the model; T. Dull, M. Kelly and A. Follenzi for help with vector construction and production; G. Cusella for help with histology; U. Matzner for the hARSA antibody and suggestions for the immunocapture assay; and L. Wrabetz, A. Malgaroli, R. Brambilla and A. Mallamaci for helpful comments and critical reading of the manuscript. This work was supported by grants form Telethon, Italy, and from the Associazione Malattie Rare Mauro Baschirotto.

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Correspondence to Claudio Bordignon.

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Consiglio, A., Quattrini, A., Martino, S. et al. In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice. Nat Med 7, 310–316 (2001). https://doi.org/10.1038/85454

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