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

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 2

Correction of sulfatide storage and neuronal damage in the CNS of GT-treated mice.

Options: View larger image (or click on image) Download as PowerPoint
Correction of sulfatide storage and neuronal damage in the CNS of GT-tre...
Transverse semithin sections of the hippocampal CA2–3 regions (A and B) and fimbria (C), the cerebellar Purkinje cell layer (D and E), and white matter (F) of untreated and mock-treated Arsa–/– mice (6 and 12 months old, as indicated), and 12-month-old GT mice. Cells with pathological features were already detectable in the pyramidal cell layer of the hippocampus and in the Purkinje cell layer of cerebellum at 6 months (left panels). Lipid storage (arrowheads) was detected throughout the white matter, particularly in the fimbria and cerebellum. The neuronal damage became more severe and the number and size of metachromatic deposits increased significantly in 12-month-old mice (central panels). A marked reduction of sulfatide-containing metachromatic granuli in the white matter and of neuronal damage in CA2–3 and in the Purkinje cell layer was observed in GT mice (right panels). Scale bar: 120 μm (A and D); 80 μm (B, C, and F); and 50 μm (E). (G) Morphometric analysis of neuronal damage, shown as percentage of total counted neurons. Neurons in the CA2–3 and in the Purkinje cell layer were protected from age-related degeneration. In 12-month-old group B treated mice, reduction of degenerating neurons as compared with that of 6-month-old untreated mice was observed, indicating neuronal rescue (*P < 0.05).