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.
View: Text | PDF
Research Article Genetics Article has an altmetric score of 9

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

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

×

Figure 1

Enzymatic reconstitution and correction of neurological defects in Arsa–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Enzymatic reconstitution and correction of neurological defects in Arsa–...
(A) ARSA activity in PBMC (left y axis) and LV content in BM (right y axis) of untreated (Arsa–/–), mock-treated (GFP), and GT-treated (pool and groups A and B) Arsa–/– mice and WT controls. ARSA activity is expressed as fold increase compared with WT levels and LV content in CpC. (B) ARSA activity (left y axis) and LV CpC (right y axis) from liver samples from the same groups as in A. (C) ARSA activity of brain extracts is expressed as percentage of WT values. For statistical analysis, see Table 1. (D) Representative TLC gel from Rh-sulfatide test on liver and brain extracts from the indicated mice groups. (E) Assessment of central motor conduction in untreated and mock-treated Arsa–/– mice, 12-month-old GT mice (pool), and age-matched WT controls (n = 15 mice per group). The GT group showed significantly lower CCT as compared with 6-month-old and age-matched Arsa–/– mice; comparison with WT mice showed normalization of CCT (*P < 0.05, **P < 0.01). (F) Behavioral evaluations of GT mice. Mean latencies on rotarod ± SEM for each day are indicated. The GT group was indistinguishable from age-matched WT controls (left panel). Twelve-month-old GT mice in group B had a significantly improved performance compared with 6-month-old Arsa–/– mice, demonstrating correction of the neurological deficit present at the time of treatment (right panel). For statistical analysis, see Table 3 (n = 15–30 mice per group.). GalCer, galactosylceramide.