Human Molecular Genetics Advance Access originally published online on August 19, 2008
Human Molecular Genetics 2008 17(22):3437-3445; doi:10.1093/hmg/ddn237
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Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in 
-mannosidosis mice
1 Biochemical Institute 2 Anatomical Institute, University of Kiel, D-24098 Kiel, Germany 3 Laboratory of Biological Psychology, University of Leuven, B-3000 Leuven, Belgium 4 Unité Mixte de Recherche CNRS/USTL 8576, Glycobiologie Structurale et Fonctionnelle, Université des Sciences et Technologies de Lille, France 5 Zymenex A/S, Roskildevej 12C, 3400 Hillerød, Denmark
* To whom correspondence should be addressed at: Biochemical Institute, Christian-Albrechts-University Kiel, Olshausenstr. 40, D-24098 Kiel, Germany. Tel: +49 4318802216; Fax: +49 4318802238; Email: psaftig{at}biochem.uni-kiel.de
Received July 3, 2008; Accepted August 7, 2008
Despite the progress in the treatment of lysosomal storage disorders (LSDs) mainly by enzyme replacement therapy, only limited success was reported in targeting the appropriate lysosomal enzyme into the brain. This prevents efficient clearance of neuronal storage, which is present in many of these disorders including 
-mannosidosis. Here we show that the neuropathology of a mouse model for -mannosidosis can be efficiently treated using recombinant human -mannosidase (rhLAMAN). After intravenous administration of different doses (25–500 U/kg), rhLAMAN was widely distributed among tissues, and immunohistochemistry revealed lysosomal delivery of the injected enzyme. Whereas low doses (25 U/kg) led to a significant clearance (<70%) in visceral tissues, higher doses were needed for a clear effect in central and peripheral nervous tissues. A distinct reduction (<50%) of brain storage required repeated high-dose injections (500 U/kg), whereas lower doses (250 U/kg) were sufficient for clearance of stored substrates in peripheral neurons of the trigeminal ganglion. Successful transfer across the blood-brain barrier was evident as the injected enzyme was found in hippocampal neurons, leading to a nearly complete disappearance of storage vacuoles. Importantly, the decrease in neuronal storage in the brain correlated with an improvement of the neuromotor disabilities found in untreated -mannosidosis mice. Uptake of rhLAMAN seems to be independent of mannose-6-phosphate receptors, which is consistent with the low phosphorylation profile of the enzyme. These data suggest that high-dose injections of low phosphorylated enzymes might be an interesting option to efficiently treat LSDs with CNS involvement.