Human Molecular Genetics Advance Access originally published online on July 21, 2004
Human Molecular Genetics 2004 13(18):1979-1988; doi:10.1093/hmg/ddh220
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Human Molecular Genetics, Vol. 13, No. 18 © Oxford University Press 2004; all rights reserved
Efficacy of enzyme replacement therapy in 
-mannosidosis mice: a preclinical animal study
1Georg-August-Universität Göttingen, Abt. Biochemie II, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany, 2Anatomisches Institut, University Kiel, Otto-Hahn-Platz 8, 24043 Kiel, Germany, 3Dipartimento di Scienze Biochimiche e Biotecnologie Molecolari, Università degli Studi di Perugia, Via del Giochetto, 06126 Perugia, Italy, 4Hemebiotech A/S, Roskildevej 12C, 3400 Hillerød, Denmark, 5Department of Medical Biochemistry IMB, University of Tromsø, N 9037 Tromsø, Norway and 6Christian-Albrecht-Universität, Institut für Biochemie, Olshausenstr. 40, 24098 Kiel, Germany
Received April 6, 2004; Revised June 29, 2004; Accepted July 13, 2004
-Mannosidosis is a lysosomal storage disorder which manifests itself in the excessive storage of mannose-containing oligosaccharides in the lysosomes of multiple peripheral tissues and in the brain. Here we report on the correction of storage in a mouse model of -mannosidosis after intravenous administration of lysosomal acid -mannosidase (LAMAN) from bovine kidney, and human and mouse recombinant LAMAN. The bovine and the human enzyme were barely phosphorylated, whereas the bulk of the mouse LAMAN contained mannose 6-phosphate recognition markers. The clearance decreased from bovine to human to mouse LAMAN with plasma half-times of 4, 8 and 12 min, respectively. The apparent half-life of the internalized enzyme was dependent on the enzyme source as well as tissue type and varied between 3 and 16 h. The corrective effect on the storage of neutral oligosaccharides was time-, tissue- and dose-dependent, and the effects were observed to be transient. After a single dose of LAMAN the maximum corrective effect was observed between 2 and 6 days after injection. In general the corrective effect of the human LAMAN was higher than that of the mouse LAMAN and lowest for the bovine LAMAN. Injection of 250 mU human LAMAN/g body weight followed by a subsequent injection 3.5 days later was sufficient to clear liver, kidney and heart from neutral oligosaccharides. Surprisingly a decrease in mannose containing oligosaccharides was also observed in the brain, with storage levels reported at <30% than that found in controls. These data clearly underline the efficacy of enzyme replacement therapy for the correction of storage in -mannosidosis and suggest that this treatment can substantially decrease storage in the brain.
* To whom correspondence should be addressed. Tel: +49 551395948; Fax: +49 551395947; Email: kfigura{at}gwdg.de
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