Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in alpha-mannosidosis mice.
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 alpha-mannosidosis. Here we show that the neuropathology of a mouse model for alpha-mannosidosis can be efficiently treated using recombinant human alpha-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 alpha-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.
Blanz
Judith
J
Biochemical Institute, University of Kiel, Kiel, Germany.
Stroobants
Stijn
S
Lüllmann-Rauch
Renate
R
Morelle
Willy
W
Lüdemann
Meike
M
D'Hooge
Rudi
R
Reuterwall
Helena
H
Michalski
Jean Claude
JC
Fogh
Jens
J
Andersson
Claes
C
Saftig
Paul
P
D000818:Animals; D001259:Ataxia / Q000188:drug therapy*; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000648:ultrastructure; D014617:Vacuoles / Q000378:metabolism; D043323:alpha-Mannosidase / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008363:alpha-Mannosidosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D043323:alpha-Mannosidase