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Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations

Gene Therapy volume 9, pages 53–63 (2002)Cite this article

Abstract

Arylsulfatase A (ASA) knockout mice represent an animal model for the lysosomal storage disease metachromatic leukodystrophy (MLD). Stem cell gene therapy with bone marrow overexpressing the human ASA cDNA from a retroviral vector resulted in the expression of high enzyme levels in various tissues. Treatment partially reduces sulfatide storage in livers exceeding 18 ng ASA/mg tissue, while complete reduction was observed in livers exceeding 50 ng ASA/mg tissue. This corresponds to about 80% and 200% of normal enzyme activity. Similar values seem to apply for kidney. A partial correction of the lipid metabolism was detectable in the brain where the galactoerebroside/sulfatide ratio, which is diminished in ASA-deficient mice, increased upon treatment. This partial correction was accompanied by amelioration of neuropathology; axonal cross-sectional areas, which are reduced in deficient mice, were significantly increased in the saphenic and sciatic nerve but not in the optic nerve. Behavioral tests suggest some improvement of neuromotor abilities. The gene transfer did not delay the degeneration occurring in the acoustic ganglion of ASA-deficient animals. The limited success of the therapy appears to be due to the requirement of unexpected high levels of ASA for correction of the metabolic defect.

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Acknowledgements

We wish to thank H Simonis for excellent technical assistance. This work was supported by the Fund of Scientific Research of Flanders (No. G.0027.97) and the Bundesministerium für Bildung und Forschung (BMBF). R D'Hooge is a postdoctoral fellow of the Fonds voor Wetenschappelijk Onderzoek (FWO).

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Authors and Affiliations

  1. Institut für Physiologische Chemie, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany

    U Matzner & V Gieselmann

  2. Anatomisches Institut, Christian-Albrechts-Universität, Kiel, Germany

    D Hartmann, R Lüllmann-Rauch, R Coenen & F Rothert

  3. Institute of Clinical Neuroscience, Section of Experimental Neuroscience, Sahlgren's University Hospital, Mölndal, Sweden

    J-E Månsson & P Fredman

  4. Laboratory of Neurochemistry and Behavior, Born Bunge Foundation, University of Antwerpen, Antwerpen, Belgium

    R D'Hooge & PP De Deyn

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Matzner, U., Hartmann, D., Lüllmann-Rauch, R. et al. Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations. Gene Ther 9, 53–63 (2002). https://doi.org/10.1038/sj.gt.3301593

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