Journal Article

Efficacy of enzyme replacement therapy in α-mannosidosis mice: a preclinical animal study

Diego Prieto Roces, Renate Lüllmann-Rauch, Jianhe Peng, Chiara Balducci, Claes Andersson, Ole Tollersrud, Jens Fogh, Aldo Orlacchio, Tommaso Beccari, Paul Saftig and Kurt von Figura

in Human Molecular Genetics

Volume 13, issue 18, pages 1979-1988
Published in print September 2004 | ISSN: 0964-6906
Published online July 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh220
Efficacy of enzyme replacement therapy in α-mannosidosis mice: a preclinical animal study

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α-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 α-mannosidosis after intravenous administration of lysosomal acid α-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 α-mannosidosis and suggest that this treatment can substantially decrease storage in the brain.

Journal Article.  6956 words.  Illustrated.

Subjects: Genetics and Genomics

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