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Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice
Alessandra Biffi, … , Angelo Quattrini, Luigi Naldini
Alessandra Biffi, … , Angelo Quattrini, Luigi Naldini
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):3070-3082. https://doi.org/10.1172/JCI28873.
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Research Article Genetics Article has an altmetric score of 9

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

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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.

Authors

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

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Figure 5

Enzyme biodistribution in neurogenic areas of the CNS and in the PNS of GT-treated mice.

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Enzyme biodistribution in neurogenic areas of the CNS and in the PNS of ...
Immunofluorescence and confocal analysis of brain (A–C), sciatic nerve (D), and DRG (E) sections of representative mice. Single confocal planes and orthoprojections acquired in Z-stack are shown from individual and merged fluorescent signals. (A–C) The ARSA-HA was found in adult neural stem cell areas, such as in the hippocampus (A and B), within different cell types, including NeuN, GFAP- and nestin-positive cells, and in the subventricular zone (C), within GFAP-positive and nestin-positive cells. (D and E) In the PNS, ARSA-HA was detected in S100-positive SCs in the sciatic nerve (D) as well as in sensory neurons in DRG (E). Scale bar: 60 μm (A); 50 μm (E); 40 μm (B and C); and 15 μm (D). TPIII, Topro III.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 12 patents
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