title: Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis.
abstract: GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal beta-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective therapy. Substrate reduction therapy (SRT) could be of potential benefit. The imino sugars N-butyldeoxynojirimycin (NB-DNJ, miglustat, Zavesca) and N-butyldeoxygalactonojirimycin (NB-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of NB-DNJ and NB-DGJ in the beta-galactosidase knockout mouse. NB-DGJ was better tolerated than NB-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by NB-DNJ. However, functional improvement was greatest with NB-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of NB-DNJ.
authors.affiliation: Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Elliot-Smith
authors.forename: Anneliese O
authors.initials: AO
authors.lastname: Speak
authors.forename: Emyr
authors.initials: E
authors.lastname: Lloyd-Evans
authors.forename: David A
authors.initials: DA
authors.lastname: Smith
authors.forename: Aarnoud C
authors.initials: AC
authors.lastname: van der Spoel
authors.forename: Mylvaganam
authors.initials: M
authors.lastname: Jeyakumar
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005243:Feces / Q000737:chemistry; D016537:Gangliosidosis, GM1 / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D017485:1-Deoxynojirimycin; C059896:miglustat; C090092:migalastat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D001616:beta-Galactosidase