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, Paul Saftig*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3437-3445
Number of pages9
JournalHuman molecular genetics
Issue number22
StatePublished - 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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