Abstract
Gaucher disease type 1, the most prevalent lysosomal storage disease, is caused by the defective activity of the lysosomal enzyme, acidβ-glucosidase, or glucocerebrosidase. Infusion of purified acidβ-glucosidase containing α-mannosyl-terminated oligosaccharides(alglucerase) is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations. The murine tissue distribution and turnover of bolus injections of alglucerase was evaluated by enzymatic activity, quantitative cross-reacting immunologic material analyses, and immunofluorescence studies. Enzyme activity measurements detected distribution to liver, spleen, thymus, kidney, and bone marrow mononuclear cells, but not to lungs and brain. In kidney and thymus, the enzyme was transiently present. In liver and spleen, enzyme activity peaked at about 20 min postinjection followed by a biphasic decrease with t½ ≈ 40-60 min and≈ 12-14 h. In bone marrow maximal enzyme activity was at 40-60 min with a disappearance t½ ≈ 60 min. Quantitative cross-reacting immunologic material studies of liver and spleen showed delivery of enzyme with decreased catalytic rate constants whose degradation included denaturation and proteolytic components. By immunofluorescence the human enzyme was distributed primarily to reticuloendothelial cells of the liver and spleen. In autopsy material from a Gaucher disease type 2 patient treated with enzyme, immunohistochemical and activity studies showed distributions similar to those in mice. These studies indicate a complex delivery and intracellular degradation of acid β-glucosidase with lower intrinsic activity than the administered therapeutic agent.
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Abbreviations
- 4MU-Glc:
-
4-methylumbelliferyl-β-D-glucopyranoside
- TX:
-
Triton X-100
- TC:
-
taurocholate
- TBS:
-
10 mM Tris, pH 7.6, 150 mM NaCl
- T-TBS:
-
TBS + 0.05% Tween 20
- CRIM:
-
cross-reacting immunologic material
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The authors dedicate this manuscript to the fond memory of Janelle Bucher, a truly special person.
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Xu, YH., Ponce, E., Sun, Y. et al. Turnover and Distribution of Intravenously Administered Mannose-Terminated Human Acid β-Glucosidase in Murine and Human Tissues. Pediatr Res 39, 313–322 (1996). https://doi.org/10.1203/00006450-199602000-00021
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DOI: https://doi.org/10.1203/00006450-199602000-00021
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