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