Miglustat: substrate reduction therapy for glycosphingolipid lysosomal storage disorders.

Substrate reduction therapy offers a novel approach to the treatment of lysosomal storage disorders. By reducing the rate of macromolecule synthesis to a level where the residual degradative activity in the cell is sufficient to prevent substrate accumulation, it should be possible to reverse storage and storage-related pathologies. Miglustat is an N-alkylated imino sugar that acts against a number of enzymes involved in processing glycoconjugates, including the ceramide-specific glucosyltransferase, which catalyzes the initial committed step in glycosphingolipid synthesis. Miglustat could therefore be used for substrate reduction therapy in glycosphingolipid lysosomal storage disorders. This article addresses both the preclinical and clinical development of miglustat for treatment of type 1 Gaucher's disease, as well as related neuronopathic glycosphingolipidoses.