Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 369, Issue 4, Pages 1071-1075Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2008.02.125
Keywords
pharmacological chaperone; Gaucher disease; lysosomal storage disorders; glucocerebrosidase; molecular chaperone; molecular mechanisms of pharmacological action; enzyme replacement therapy
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Funding
- Intramural NIH HHS [Z01 NS002982-09] Funding Source: Medline
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Intravenous enzyme replacement therapy (ERT) with purified glucocerebrosidase (GLA) leads to significant improvement of the clinical manifestations in patients with Type 1 Gaucher disease. However, the high doses required, slow response and inability to recover most of the infused enzyme in the target tissues may be attributed to losses occurring during transit en route to the lysosome. Preincubation of GLA with isofagomine (IFG), a slow-binding inhibitor, significantly increased stability of the enzyme to heat, neutral pH and denaturing agents in vitro. Preincubation of GLA with isofagomine prior to uptake by cultured cells results in increased intracellular enzyme activity accompanied by an increase in enzyme protein suggesting that reduced denaturation of GLA in the presence of isofagomine leads to a decrease in the degradation of the enzyme after internalization. Preincubation of GLA with slow-binding inhibitors before infusion may improve the effectiveness of ERT for Gaucher disease. Published by Elsevier Inc.
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