title: Dexamethasone-mediated up-regulation of the mannose receptor improves the delivery of recombinant glucocerebrosidase to Gaucher macrophages.
abstract: 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.
authors: Genzyme Corporation, Framingham, MA 01701-9322, USA.
authors: Yunxiang
authors: Y
authors: Zhu
authors: Xuemei
authors: X
authors: Li
authors: Edward H
authors: EH
authors: Schuchman
authors: Robert J
authors: RJ
authors: Desnick
authors: Seng H
authors: SH
authors: Cheng
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005776:Gaucher Disease / Q000473:pathology*; D005938:Glucocorticoids / Q000494:pharmacology; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage; D013154:Spleen / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D003907:Dexamethasone; D005962:Glucosylceramidase; C090568:imiglucerase