title: Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease.
abstract: Glycosphingolipid (GSL) lysosomal storage disorders are inherited enzyme deficiencies that result in pathological lysosomal accumulation of glycolipids, with widespread clinical consequences. Type 1 Gaucher disease is the commonest of these; the deficient enzyme in this condition is glucocerebrosidase. Clinical manifestations include hepatosplenomegaly, thrombocytopenia, anaemia, recurrent infections and skeletal lesions. The condition can be treated with intravenous enzyme replacement therapy (ERT). Substrate reduction therapy is a new approach in which glycolipid accumulation is counteracted not by replacing the deficient enzyme but by reducing the substrate level to better balance residual activity of the deficient enzyme. Miglustat is an inhibitor of glucosylceramide synthase, a key enzyme in GSL synthesis. Oral administration of miglustat to patients with type 1 Gaucher disease attenuates the synthesis of glucocerebroside, the substrate of the deficient glucocerebrosidase. In the first clinical study, patients with type 1 Gaucher disease who had enlargement of the liver or spleen and (if present) the spleen at baseline received 12 months treatment with oral miglustat. There were mean decreases in liver and spleen volumes of 12% (7.9-16.4, p < 0.001) and 19% (14.3-23.7, p < 0.001), respectively. Mean haemoglobin increased by 0.26 g dl(-1) (-0.5-0.57, not statistically significant) and platelet count by 8.3 x 10(9) l(-1) (1.9-14.7, p = 0.014).
authors.affiliation: Oxford GlycoSciences, The Forum, 86 Milton Park, Abingdon, Oxford OX14 4RY, UK. chris.moyses@ogs.co.uk
authors.forename: Chris
authors.initials: C
authors.lastname: Moyses
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005776:Gaucher Disease / Q000188:drug therapy* / Q000378:metabolism; D005962:Glucosylceramidase / Q000627:therapeutic use*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D005962:Glucosylceramidase; C090568:imiglucerase