title: Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.
abstract: BACKGROUND
  Current treatment for Gaucher's disease involves administration of intravenous glucocerebrosidase to degrade glucocerebroside stored in lysosomes. Lowering the rate of biosynthesis of glucocerebroside should decrease accumulation of this substrate. We investigated the safety and efficacy of OGT 918 (N-butyldeoxynojirimycin), an inhibitor of glucosyltransferase, as a novel oral treatment for non-neuronopathic Gaucher's disease.
  
  
  METHODS
  We recruited, into a 1-year open-label study, 28 adults (seven with previous splenectomies) from four national Gaucher's referral clinics, who were unable or unwilling to receive enzyme treatment. We measured liver and spleen volume by computed tomography or magnetic resonance imaging at baseline and at months 6 and 12, and biochemical and haematological variables monthly, including chitotriosidase activity (a sensitive marker of Gaucher's disease activity). Patients were started on 100 mg oral OGT 918 three times daily.
  
  
  RESULTS
  Baseline liver volumes were 1.1-2.7 times normal and spleen volumes 5.1-24.8 times normal. At 12 months, mean liver and spleen volumes were significantly lowered by 12% (95% CI 7.8-16.4) and 19% (14.3-23.7), respectively (each p<0.001). Haematological variables improved slightly. Mean organ volume and blood counts improved continually between 6 months and 12 months of treatment. Mean chitotriosidase concentrations fell by 16.4% over 12 months (p<.0001). Six patients withdrew because of gastrointestinal complaints (two), personal reasons (two), or severe pre-existing disease (two). The most frequent adverse effect was diarrhoea, which occurred in 79% of patients shortly after the start of treatment.
  
  
  CONCLUSIONS
  Decrease of substrate formation by OGT 918 improves key clinical features of non-neuronopathic Gaucher's disease. The strategy justifies further trials in this and other glycosphingolipid storage disorders.
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.
authors.forename: T
authors.initials: T
authors.lastname: Cox
authors.forename: R
authors.initials: R
authors.lastname: Lachmann
authors.forename: C
authors.initials: C
authors.lastname: Hollak
authors.forename: J
authors.initials: J
authors.lastname: Aerts
authors.forename: S
authors.initials: S
authors.lastname: van Weely
authors.forename: M
authors.initials: M
authors.lastname: Hrebícek
authors.forename: F
authors.initials: F
authors.lastname: Platt
authors.forename: T
authors.initials: T
authors.lastname: Butters
authors.forename: R
authors.initials: R
authors.lastname: Dwek
authors.forename: C
authors.initials: C
authors.lastname: Moyses
authors.forename: I
authors.initials: I
authors.lastname: Gow
authors.forename: D
authors.initials: D
authors.lastname: Elstein
authors.forename: A
authors.initials: A
authors.lastname: Zimran
mesh_terms: D017485:1-Deoxynojirimycin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D003967:Diarrhea / Q000139:chemically induced; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005776:Gaucher Disease / Q000188:drug therapy*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006596:Hexosaminidases / Q000097:blood; D006801:Humans; D008099:Liver / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D013154:Spleen / Q000187:drug effects; D014057:Tomography, X-Ray Computed
chemical_list: D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases; D006596:Hexosaminidases; C086400:chitotriosidase