RT Journal Article
SR Electronic
T1 Dexamethasone-Mediated Up-Regulation of the Mannose Receptor Improves the Delivery of Recombinant Glucocerebrosidase to Gaucher Macrophages
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 705
OP 711
DO 10.1124/jpet.103.060236
VO 308
IS 2
A1 Yunxiang Zhu
A1 Xuemei Li
A1 Edward H. Schuchman
A1 Robert J. Desnick
A1 Seng H. Cheng
YR 2004
UL http://jpet.aspetjournals.org/content/308/2/705.abstract
AB Enzyme replacement therapy for Gaucher disease uses a recombinant glucocerebrosidase (Cerezyme) whose oligosaccharide chains have been remodeled to expose the core mannose residues. This modification promotes the uptake of the hydrolase by Gaucher-affected macrophages via mannose receptor-mediated endocytosis. However, studies revealed that amounts of the infused enzyme were also delivered to other mannose receptor-bearing cells such as the liver sinusoidal endothelial cells. To maximize the delivery of Cerezyme to macrophages, agents that increased the cell surface levels of the mannose receptor specifically on macrophages were examined. Treatment with dexamethasone improved the in vitro uptake of Cerezyme by a macrophage but not by liver sinusoidal endothelial or hepatocyte cell lines. The enhanced uptake by the macrophages was due to an increase in surface mannose receptors because the activity could be blocked by the addition of mannans. Pretreatment of rats with the glucocorticoid also preferentially enhanced the delivery of Cerezyme to the Kupffer cells and splenic macrophages. This effect of dexamethasone also applied to substrate-laden macrophages isolated from Niemann-Pick A mice. Together, these data suggest that pretreatment with dexamethasone could specifically enhance the presentation of mannose receptors on Gaucher macrophages with resultant improvement in delivery of the enzyme to the affected cells. The American Society for Pharmacology and Experimental Therapeutics