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Human Molecular Genetics Advance Access originally published online on March 16, 2005
Human Molecular Genetics 2005 14(9):1139-1152; doi:10.1093/hmg/ddi126
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy

Ulrich Matzner1,*, Eva Herbst2, Kerstin Khalaj Hedayati2, Renate Lüllmann-Rauch2, Carsten Wessig3, Stephan Schröder1, Carl Eistrup4, Christer Möller4, Jens Fogh4 and Volkmar Gieselmann1

1Institut für Physiologische Chemie, Rheinische Friedrich-Wilhelms Universität, Nussallee 11, 53115 Bonn, Germany, 2Anatomisches Institut, Christian-Albrechts-Universität, Otto-Hahn-Platz 8, 24043 Kiel, Germany, 3Neurologische Klinik und Poliklinik, Bayerische Julius-Maximilians Universität, Josef-Schneider-Str. 11, 97080 Würzburg, Germany and 4Zymenex A/S, Roskildevej 12C, 3400 Hillerød, Denmark and Dalénum 13, 18170 Lidingö, Sweden

* To whom correspondence should be addressed. Tel: +49 228734744; Fax: +49 228732416; Email: matzner{at}institut.physiochem.uni-bonn.de

Received January 7, 2005; Accepted March 8, 2005

A deficiency of arylsulfatase A (ASA) causes the lysosomal storage disease metachromatic leukodystrophy, which is characterized by accumulation of the sphingolipid 3-O-sulfogalactosylceramide (sulfatide). Sphingolipid storage results in progressive demyelination and severe neurologic symptoms. The disease is lethal, and curative therapy is not available. To assess the therapeutic potential of enzyme replacement therapy (ERT), ASA knockout mice were treated by intravenous injection of recombinant human ASA. Plasma levels of ASA declined with a half-time of ~40 min, and enzyme was detectable in tissues within minutes after injection. The uptake of injected enzyme was high into liver, moderate into peripheral nervous system (PNS) and kidney and very low into brain. The apparent half-life of endocytosed enzyme was ~4 days. A single injection led to a time- and dose-dependent decline of the excess sulfatide in PNS and kidney by up to 70%, but no reduction was seen in brain. Four weekly injections with 20 mg/kg body weight not only reduced storage in peripheral tissues progressively, but also were surprisingly effective in reducing sulfatide storage in brain and spinal cord. The histopathology of kidney and central nervous system was ameliorated. Improved neuromotor coordination capabilities and normalized peripheral compound motor action potential demonstrate the benefits of ERT on the nervous system function. Enzyme replacement may therefore be a promising therapeutic option in this devastating disease.


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