Substrate-reduction therapy with miglustat for glycosphingolipid storage disorders affecting the brain.

A number of lysosomal storage disorders (LSDs) are characterized by glycosphingolipid (GSL) storage in the brain. Although enzyme-replacement therapy is an effective treatment for the visceral manifestations of some of these disorders, this approach has not, to date, been useful in CNS disease. Substrate reduction therapy (SRT) is an alternative approach to treatment in which the aim is to reduce the rate of synthesis of GSL to a level where the residual enzyme activity in the affected cell can prevent lysosomal storage. Miglustat, an iminosugar, is an inhibitor of the first step of GSL synthesis and has been used successfully for SRT in Gaucher disease. Miglustat is a small molecule and can enter the brain. It has been shown to delay symptom onset and prolong life in a number of animal models of GSL LSDs. This review describes the current progress in the clinical development of SRT with miglustat for these disorders.