Lancet 2000; 355: 1481 - 1485
Timothy Cox, Robin Lachmann, Carla Hollak, Johannes Aerts, Sonja van Weely, Martin Hrebícek, Frances Platt, Terry Butters, Raymond Dwek, Chris Moyses, Irene Gow, Deborah Elstein, Ari Zimran
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK (Prof T Cox FRCP, R Lachmann MRCP); Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands (C Hollak MD, Prof J Aerts PhD, S van Weely PhD); Institute of Inherited Metabolic Disorders, Prague, Czech Republic (M Hrebícek MD); Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK (F Platt PhD, T Butters PhD, Prof R Dwek FRS); Oxford GlycoSciences, Abingdon Science Park, Oxon, UK (C Moyses MRCP, I Gow BSc); Shaare Zedek Medical Centre, Jerusalem, Israel (D Elstein PhD, A Zimran MD)
Correspondence to: Prof Timothy Cox
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 accummulation 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.
Findings 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<0·001). 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.
Interpretation 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.
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