Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice

Alessandra Biffi, Alessia Capotondo, Stefania Fasano, Ubaldo Del Carro, Sergio Marchesini, Hisaya Azuma, Maria Chiara Malaguti, Stefano Amadio, Riccardo Brambilla, Markus Grompe, Claudio Bordignon, Angelo Quattrini, Luigi Naldini

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

Metachromatic leukodystrophy (MLD) is a demyelinating lysosomal storage disorder for which new treatments are urgently needed. We previously showed that transplantation of gene-corrected hematopoietic stem progenitor cells (HSPCs) in presymptomatic myeloablated MLD mice prevented disease manifestations. Here we show that HSC gene therapy can reverse neurological deficits and neuropathological damage in affected mice, thus correcting an overt neurological disease. The efficacy of gene therapy was dependent on and proportional to arylsulfatase A (ARSA) overexpression in the microglia progeny of transplanted HSPCs. We demonstrate a widespread enzyme distribution from these cells through the CNS and a robust cross-correction of neurons and glia in vivo. Conversely, a peripheral source of enzyme, established by transplanting ARSA-overexpressing hepatocytes from transgenic donors, failed to effectively deliver the enzyme to the CNS. These results indicate that the recruitment of gene-modified, enzyme-overexpressing microglia makes the enzyme bioavailable to the brain and makes therapeutic efficacy and disease correction attainable. Overall, our data provide a strong rationale for implementing HSPC gene therapy in MLD patients.

Original languageEnglish (US)
Pages (from-to)3070-3082
Number of pages13
JournalJournal of Clinical Investigation
Volume116
Issue number11
DOIs
StatePublished - Nov 1 2006

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Metachromatic Leukodystrophy
Hematopoietic Stem Cells
Genetic Therapy
Cerebroside-Sulfatase
Enzymes
Microglia
Cell- and Tissue-Based Therapy
Neuroglia
Genes
Hepatocytes
Transplantation
Tissue Donors
Neurons
Brain
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Biffi, A., Capotondo, A., Fasano, S., Del Carro, U., Marchesini, S., Azuma, H., ... Naldini, L. (2006). Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. Journal of Clinical Investigation, 116(11), 3070-3082. https://doi.org/10.1172/JCI28873

Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. / Biffi, Alessandra; Capotondo, Alessia; Fasano, Stefania; Del Carro, Ubaldo; Marchesini, Sergio; Azuma, Hisaya; Malaguti, Maria Chiara; Amadio, Stefano; Brambilla, Riccardo; Grompe, Markus; Bordignon, Claudio; Quattrini, Angelo; Naldini, Luigi.

In: Journal of Clinical Investigation, Vol. 116, No. 11, 01.11.2006, p. 3070-3082.

Research output: Contribution to journalArticle

Biffi, A, Capotondo, A, Fasano, S, Del Carro, U, Marchesini, S, Azuma, H, Malaguti, MC, Amadio, S, Brambilla, R, Grompe, M, Bordignon, C, Quattrini, A & Naldini, L 2006, 'Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice', Journal of Clinical Investigation, vol. 116, no. 11, pp. 3070-3082. https://doi.org/10.1172/JCI28873
Biffi A, Capotondo A, Fasano S, Del Carro U, Marchesini S, Azuma H et al. Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. Journal of Clinical Investigation. 2006 Nov 1;116(11):3070-3082. https://doi.org/10.1172/JCI28873
Biffi, Alessandra ; Capotondo, Alessia ; Fasano, Stefania ; Del Carro, Ubaldo ; Marchesini, Sergio ; Azuma, Hisaya ; Malaguti, Maria Chiara ; Amadio, Stefano ; Brambilla, Riccardo ; Grompe, Markus ; Bordignon, Claudio ; Quattrini, Angelo ; Naldini, Luigi. / Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 11. pp. 3070-3082.
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