title: Isofagomine increases lysosomal delivery of exogenous glucocerebrosidase.
abstract: 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.
authors.affiliation: Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 3D04, 9000 Rockville Pike, Bethesda, MD 20892-1260, USA.
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Shen
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Edwards
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Hong
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Murray
mesh_terms: D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004795:Enzyme Stability / Q000187:drug effects; D005776:Gaucher Disease / Q000188:drug therapy; D005962:Glucosylceramidase / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D050112:Imino Pyranoses / Q000494:pharmacology; D008247:Lysosomes / Q000201:enzymology*; D008264:Macrophages / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011489:Protein Denaturation
chemical_list: D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; D010880:Piperidines; C098432:isofagomine; D005962:Glucosylceramidase