Skip Navigation


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
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/9/1139    most recent
ddi126v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (40)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Matzner, U.
Right arrow Articles by Gieselmann, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Matzner, U.
Right arrow Articles by Gieselmann, V.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
U. Matzner, B. Breiden, G. Schwarzmann, A. Yaghootfam, A. L. Fluharty, A. Hasilik, K. Sandhoff, and V. Gieselmann
Saposin B-dependent Reconstitution of Arylsulfatase A Activity in Vitro and in Cell Culture Models of Metachromatic Leukodystrophy
J. Biol. Chem., April 3, 2009; 284(14): 9372 - 9381.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. Blanz, S. Stroobants, R. Lullmann-Rauch, W. Morelle, M. Ludemann, R. D'Hooge, H. Reuterwall, J. C. Michalski, J. Fogh, C. Andersson, et al.
Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in {alpha}-mannosidosis mice
Hum. Mol. Genet., November 15, 2008; 17(22): 3437 - 3445.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. H. Grubb, C. Vogler, B. Levy, N. Galvin, Y. Tan, and W. S. Sly
Chemically modified {beta}-glucuronidase crosses blood-brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII
PNAS, February 19, 2008; 105(7): 2616 - 2621.
[Abstract] [Full Text] [PDF]

Home page
 J Child NeurolHome page
M. Gorg, W. Wilck, B. Granitzny, A. Suerken, Z. Lukacs, Xiaoqi Ding, M. Schulte-Markwort, and A. Kohlschutter
Stabilization of Juvenile Metachromatic Leukodystrophy After Bone Marrow Transplantation: A 13-Year Follow-up
J Child Neurol, September 1, 2007; 22(9): 1139 - 1142.
[Abstract] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. Urayama, J. H. Grubb, W. A. Banks, and W. S. Sly
Epinephrine enhances lysosomal enzyme delivery across the blood brain barrier by up-regulation of the mannose 6-phosphate receptor
PNAS, July 31, 2007; 104(31): 12873 - 12878.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
W. S. Sly, C. Vogler, J. H. Grubb, B. Levy, N. Galvin, Y. Tan, T. Nishioka, and S. Tomatsu
Enzyme therapy in mannose receptor-null mucopolysaccharidosis VII mice defines roles for the mannose 6-phosphate and mannose receptors
PNAS, October 10, 2006; 103(41): 15172 - 15177.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
C. Sevin, A. Benraiss, D. Van Dam, D. Bonnin, G. Nagels, L. Verot, I. Laurendeau, M. Vidaud, V. Gieselmann, M. Vanier, et al.
Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy
Hum. Mol. Genet., January 1, 2006; 15(1): 53 - 64.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.