Biodistribution, kinetics, and efficacy of highly phosphorylated and non-phosphorylated beta-glucuronidase in the murine model of mucopolysaccharidosis VII
Ms. Sands et al., Biodistribution, kinetics, and efficacy of highly phosphorylated and non-phosphorylated beta-glucuronidase in the murine model of mucopolysaccharidosis VII, J BIOL CHEM, 276(46), 2001, pp. 43160-43165
Enzyme replacement therapy (ERT) has been shown to be effective at reducing
the accumulation of undegraded substrates in lysosomal storage diseases. M
ost ERT studies have been performed with recombinant proteins that are mixt
ures of phosphorylated and nonphosphorylated enzyme. Because different cell
types use different receptors to take up phosphorylated or non-phosphoryla
ted enzyme, it is difficult to determine which form of enzyme contributed t
o the clinical response. Here we compare the uptake, distribution, and effi
cacy of highly phosphorylated and non-phosphorylated P-glucuronidase (GUSB)
in the MPS VII mouse. Highly phosphorylated murine GUSB was efficiently ta
ken up by a wide range of tissues. In contrast, nonphosphorylated murine GU
SB was taken up primarily by tissues of the reticuloendothelial (RE) system
. Although the tissue distribution was different, the half-lives of both en
zymes in any particular tissue were similar. Both preparations of enzyme we
re capable of preventing the accumulation of lysosomal storage in cell type
s they targeted. An important difference in clinical efficacy emerged in th
at phosphorylated GUSB was more efficient than non-phosphorylated enzyme at
preventing the hearing loss associated with this disease. These data sugge
st that both forms of enzyme contribute to the clinical responses of ERT in
MPS VII mice but that enzyme preparations containing phosphorylated GUSB a
re more broadly effective than non-phosphorylated enzyme.