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

Antonella Consiglio, Angelo Quattrini, Sabata Martino, Jean Charles Bensadoun, Diego Dolcetta, Alessandra Trojani, Giuliana Benaglia, Sergio Marchesini, Vincenzo Cestari, Alberto Oliverio, Claudio Bordignon, Luigi Naldini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)310-316
Number of pages7
JournalNature Medicine
Volume7
Issue number3
DOIs
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Consiglio, A., Quattrini, A., Martino, S., Bensadoun, J. C., Dolcetta, D., Trojani, A., Benaglia, G., Marchesini, S., Cestari, V., Oliverio, A., Bordignon, C., & Naldini, L. (2001). In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: Correction of neuropathology and protection against learning impairments in affected mice. Nature Medicine, 7(3), 310-316. https://doi.org/10.1038/85454