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

Abstract

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.

Keywords::

• enzyme-replacement therapy
• Gaucher disease
• glycosphingolipidosis
• GM2 gangliosidosis
• lysosomal storage disorder
• miglustat
• Niemann–Pick disease
• Sandhoff disease
• substrate-reduction therapy
• Tay–Sachs disease

Financial & competing interests disclosure

Robin Lachmann has received honoraria, consulting fees and unrestricted educationl grants from Actelion and Genzyme. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.