T. Cox et al., Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis, LANCET, 355(9214), 2000, pp. 1481-1485
Citations number
22
Categorie Soggetti
General & Internal Medicine","Medical Research General Topics
Background Current treatment for Gaucher's disease involves administration
of intravenous glucocerebrosidase to degrade glucocerebroside stored in lys
osomes. Lowering the rate of biosynthesis of glucocerebroside should decrea
se 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 an
d spleen volume by computed tomography or magnetic resonance imaging at bas
eline 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 tim
es daily,
Findings Baseline liver volumes were 1.1-2.7 times normal and spleen volume
s 5.1-24.8 times normal. At 12 months, mean liver and spleen Volumes were s
ignificantly lowered by 12% (95% CI 7.8-16.4) and 19% (14.3-23.7), respecti
vely (each p<0001). 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 mo
nths (p<0.001). Six patients withdrew because of gastrointestinal complaint
s (two), personal reasons (two), or severe preexisting disease (two). The m
ost frequent adverse effect was diarrhoea, which occurred in 79% of patient
s shortly after the start of treatment.
Interpretation Decrease of substrate formation by OGT 918 improves key clin
ical features of non-neuronopathic Gaucher's disease. The strategy justifie
s further trials in this and other glycosphingolipid storage disorders.