Journal Article

Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in α-mannosidosis mice

Judith Blanz, Stijn Stroobants, Renate Lüllmann-Rauch, Willy Morelle, Meike Lüdemann, Rudi D'Hooge, Helena Reuterwall, Jean Claude Michalski, Jens Fogh, Claes Andersson and Paul Saftig

in Human Molecular Genetics

Volume 17, issue 22, pages 3437-3445
Published in print November 2008 | ISSN: 0964-6906
Published online August 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn237
Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in α-mannosidosis mice

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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 α-mannosidosis. Here we show that the neuropathology of a mouse model for α-mannosidosis can be efficiently treated using recombinant human α-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 α-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.

Journal Article.  5572 words.  Illustrated.

Subjects: Genetics and Genomics

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