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Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells
Alessandra Biffi, … , Claudio Bordignon, Luigi Naldini
Alessandra Biffi, … , Claudio Bordignon, Luigi Naldini
Published April 15, 2004
Citation Information: J Clin Invest. 2004;113(8):1118-1129. https://doi.org/10.1172/JCI19205.
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Article Genetics Article has an altmetric score of 12

Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells

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Abstract

Gene-based delivery can establish a sustained supply of therapeutic proteins within the nervous system. For diseases characterized by extensive CNS and peripheral nervous system (PNS) involvement, widespread distribution of the exogenous gene may be required, a challenge to in vivo gene transfer strategies. Here, using lentiviral vectors (LVs), we efficiently transduced hematopoietic stem cells (HSCs) ex vivo and evaluated the potential of their progeny to target therapeutic genes to the CNS and PNS of transplanted mice and correct a neurodegenerative disorder, metachromatic leukodystrophy (MLD). We proved extensive repopulation of CNS microglia and PNS endoneurial macrophages by transgene-expressing cells. Intriguingly, recruitment of these HSC-derived cells was faster and more robust in MLD mice. By transplanting HSCs transduced with the arylsulfatase A gene, we fully reconstituted enzyme activity in the hematopoietic system of MLD mice and prevented the development of motor conduction impairment, learning and coordination deficits, and neuropathological abnormalities typical of the disease. Remarkably, ex vivo gene therapy had a significantly higher therapeutic impact than WT HSC transplantation, indicating a critical role for enzyme overexpression in the HSC progeny. These results indicate that transplantation of LV-transduced autologous HSCs represents a potentially efficacious therapeutic strategy for MLD and possibly other neurodegenerative disorders.

Authors

Alessandra Biffi, Michele De Palma, Angelo Quattrini, Ubaldo Del Carro, Stefano Amadio, Ilaria Visigalli, Maria Sessa, Stefania Fasano, Riccardo Brambilla, Sergio Marchesini, Claudio Bordignon, Luigi Naldini

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Figure 4

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Enhanced migration and activated morphology of vector-expressing cells i...
Enhanced migration and activated morphology of vector-expressing cells in the CNS of As2–/– MLD mice. (A) Cryostatic sections of the corpus callosum of a representative transplanted MLD mouse 6 months after BMT, showing widespread GFP+ cells with a swollen ameboid morphology and coexpressing F4/80. Scale bar: 80 μm. (B) Cryostatic sections from the hippocampus of the same mouse were first immunostained as in A, examined under the fluorescent microscope (three panels on the left) and then stained with PAS (panel on the far right). The GFP+, F4/80+ microglia cells were PAS-reactive, indicating their content of lipid storage granules. Scale bar: 40 μm.

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

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