The therapeutic options for lysosomal storage diseases (LSDs) have expanded greatly over the past decade, although for many disorders there is still no effective treatment. Given that the majority of LSDs involve pathological changes in both the brain and peripheral tissues, effective treatment of central nervous system (CNS) and peripheral manifestations still remains a considerable technical challenge. Type 1 Gaucher disease has two approved treatment modalities - enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) - which have unique, independent and potentially complementary mechanisms of action. The availability of these two therapies has greatly increased the options for the effective clinical management of type 1 Gaucher disease. ERT involves the intravenous administration of fully functional enzyme that is taken up by cells and delivered to the lysosome, where it can compensate for the underlying enzyme deficiency. SRT uses an orally available, small molecule drug that inhibits the first committed step in glycosphingolipid biosynthesis. The aim is to reduce the rate of biosynthesis of glycosphingolipids to offset the catabolic defect, restoring the balance between the rate of biosynthesis and the rate of catabolism. SRT also has the potential to treat LSDs with CNS pathology, as the drug in clinical use (miglustat, Zavesca; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) crosses the blood-brain barrier. In this review, the current status of SRT for the treatment of Gaucher disease and other LSDs will be discussed, based upon preclinical and clinical studies.
Conclusion: SRT is an oral alternative treatment option for patients with type 1 Gaucher disease unwilling or unable to receive ERT. With the recent reports of clinical improvement/stabilization of CNS manifestations following SRT in patients with Niemann-Pick disease type C, miglustat may also have a role to play in the management of patients with glycosphingolipid storage in the brain. Furthermore, as SRT synergises with other therapeutic modalities, it may also prove to be a key component of combination therapies in the future.