Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Substrate reduction therapy is a novel approach to treating glycosphingolipid (GSL) lysosomal storage disorders. These diseases are caused by mutations in the genes coding for enzymes involved in GSL catabolism and are characterised by the accumulation of GSL substrates within the lysosomes of cells. The aim of substrate reduction therapy is to inhibit the rate of synthesis of GSLs to levels where the residual activity of the mutant catabolic enzyme is sufficient to prevent pathological storage. In this review we discuss the development of N-butyldeoxynojirimycin (NB-DNJ), an imino sugar that inhibits the ceramide-specific glucosyltransferase which catalyses the first committed step of GSL synthesis. This agent has been shown to slow accumulation of stored glycolipid in an in vitro model of Gaucher's disease and in knockout mouse models of Tay-Sachs and Sandhoff diseases. Furthermore, administration of NB-DNJ to Sandhoff mice delays the onset of neurological disease and also slows its progression. We discuss safety and efficacy data from the clinical trial of substrate reduction with NB-DNJ which has been undertaken in patients with Type 1 Gaucher's disease. This trial provides a proof-of-principle for the use of this approach in a wide range of GSL lysosomal storage diseases.

Original publication

DOI

10.1517/13543784.10.3.455

Type

Journal article

Journal

Expert Opin Investig Drugs

Publication Date

03/2001

Volume

10

Pages

455 - 466

Keywords

1-Deoxynojirimycin, Animals, Glycosphingolipids, Humans, Lysosomal Storage Diseases, Mice