title: Substrate reduction therapy of glycosphingolipid storage disorders.
abstract: In the last 15 years enormous progress has been made regarding therapy of type I Gaucher disease, a severely disabling disorder characterized by intralysosomal storage of glucosylceramide in tissue macrophages. Effective enzyme replacement therapy of type I Gaucher disease, based on chronic intravenous administration of mannose-terminated recombinant human glucocerebrosidase, has been available since 1990 and has been applied in several thousand patients without serious adverse effects. An alternative therapeutic approach, so-called substrate reduction therapy, is based on partial reduction of the synthesis of glucosylceramide and hence of subsequent metabolites. Oral administration of an inhibitor of glucosylceramide synthesis (N-butyldeoxynojirimycin, registered in Europe since 2002 as miglustat (Zavesca)), is effective in reversing clinical symptoms in type I Gaucher patients with mild to moderate disease manifestations. The growing long-term experience with substrate reduction therapy indicates that this treatment is also without major adverse effects. Substrate reduction therapy, in conjunction with enzyme replacement therapy, may play an important role in the future clinical management of patients suffering from type I Gaucher disease. Clinical trials are under way that should reveal the value of substrate reduction for maintenance therapy of type I Gaucher disease and for treatment of neuronopathic variants of Gaucher disease, Niemann-Pick disease type C, late-onset Tay-Sachs disease and Sandhoff disease.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands. j.m.aerts@amc.uva.nl
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Carla E M
authors.initials: CE
authors.lastname: Hollak
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.forename: Johanna E M
authors.initials: JE
authors.lastname: Groener
authors.forename: Mario
authors.initials: M
authors.lastname: Maas
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005776:Gaucher Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism*; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000188:drug therapy / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D017410:Practice Guidelines as Topic; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D009025:Morpholines; D011994:Recombinant Proteins; D017485:1-Deoxynojirimycin; C070292:alglucerase; C033110:RV 538; C059896:miglustat; C090092:migalastat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D005962:Glucosylceramidase