{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T12:59:28Z","timestamp":1761310768216},"reference-count":70,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,3,24]],"date-time":"2012-03-24T00:00:00Z","timestamp":1332547200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The success of enzymatic replacement in Gaucher disease has stimulated development of targeted protein replacement for other lysosomal disorders, including Anderson\u2010Fabry disease, which causes fatal cardiac, cerebrovascular and renal injury: deficiency of lysosomal \u03b1\u2010Galactosidase A induces accumulation of glycosphingolipids. Endothelial cell storage was the primary endpoint in a clinical trial that led to market authorization. Two \u03b1\u2010Galactosidase A preparations are licensed worldwide, but fatal outcomes persist, with storage remaining in many tissues. We compare mechanisms of uptake of \u03b1 \u2010Galactosidase A into cells relevant to Fabry disease, in order to investigate if the enzyme is targeted to the lysosomes in a mannose\u20106\u2010phosphate receptor dependent fashion, as generally believed. \u03b1 \u2010Galactosidase A uptake was examined in fibroblasts, four different endothelial cell models, and hepatic cells in vitro. Uptake of europium\u2010labeled human \u03b1 \u2010Galactosidase A was measured by time\u2010resolved fluorescence. Ligand\u2010specific uptake was quantified in inhibitor studies. Targeting to the lysosome was determined by precipitation and by confocal microscopy. The quantity and location of cation\u2010independent mannose\u20106\u2010phosphate receptors in the different cell models were investigated using confocal microscopy. Uptake and delivery of \u03b1 \u2010Galactosidase A to lysosomes in fibroblasts is mediated by the canonical mannose\u20106\u2010phosphate receptor pathway, but in endothelial cells in vitro this mechanism does not operate. Moreover, this observation is supported by a striking paucity of expression of cation independent mannose\u20106\u2010phosphate receptors on the plasma membrane of the four endothelial cell models and by little delivery of enzyme to lysosomes, when compared with fibroblasts. If these observations are confirmed in vivo, alternative mechanisms will be needed to explain the ready clearance of storage from endothelial cells in patients undergoing enzyme replacement therapy.<\/jats:p>","DOI":"10.1007\/s10545-012-9472-3","type":"journal-article","created":{"date-parts":[[2012,3,23]],"date-time":"2012-03-23T16:53:26Z","timestamp":1332521606000},"page":"1107-1117","source":"Crossref","is-referenced-by-count":14,"title":["Lysosomal delivery of therapeutic enzymes in cell models of Fabry disease"],"prefix":"10.1002","volume":"35","author":[{"given":"D.","family":"Marchesan","sequence":"first","affiliation":[{"name":"Department of Medicine Addenbrooke's Hospital University of Cambridge Hills Road Cambridge CB2 0QQ UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T. 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