Biodistribution, kinetics, and efficacy of highly phosphorylated and non-phosphorylated beta-glucuronidase in the murine model of mucopolysaccharidosis VII

Citation
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
Citations number
40
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
46
Year of publication
2001
Pages
43160 - 43165
Database
ISI
SICI code
0021-9258(20011116)276:46<43160:BKAEOH>2.0.ZU;2-W
Abstract
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.