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Human Molecular Genetics Advance Access published online on March 16, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi126
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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

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

Ulrich Matzner 1*, Eva Herbst 2, Kerstin Khalaj Hedayati 2, Renate Lüllmann-Rauch 2, Carsten Wessig 3, Stephan Schröder 1, Carl Eistrup 4, Christer Möller 4, Jens Fogh 4, and Volkmar Gieselmann 1

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

* To whom correspondence should be addressed.
Ulrich Matzner, E-mail: matzner{at}institut.physiochem.uni-bonn.de


  Abstract

A deficiency of arylsulfatase A 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 arylsulfatase A knockout mice were treated by intravenous injection of recombinant human arylsulfatase A. Plasma levels of arylsulfatase A 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 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 peripheral nervous system and kidney by up to 70%, but no reduction was seen in brain. Four weekly injections with 20 mg/kg body weight did not only reduce storage in peripheral tissues progressively, but were surprisingly also effective in reducing sulfatide storage in the 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 enzyme replacement therapy on the nervous system function. Enzyme replacement may therefore be a promising therapeutic option in this devastating disease.


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