Clinical experience with substrate reduction therapy.

The introduction of substrate reduction therapy (SRT) using miglustat (Zavesca(R)) gives physicians and patients a choice of treatment options for type 1 Gaucher's disease. Enzyme replacement therapy (ERT) has proven a successful approach to treating the haematologic abnormalities and organomegaly. However, long-term complications such as skeletal disease and subtle abnormalities in the nervous system do not respond as well, if at all, to ERT. The basic concept behind ERT is acceleration of the degradation of accumulated cerebroside. In contrast, SRT prevents the accumulation of glucocerebroside by inhibiting the enzyme responsible for its synthesis. We have used the European Working Group on Gaucher's disease guidelines as a basis for switching patients, all of whom had previously been treated with ERT, to miglustat. Our initial experience with our cohort of six patients with type I Gaucher's disease indicates that oral miglustat provides an effective alternative for patients unsuitable for ERT. The successful use of enzyme replacement therapy over the past decade has completely changed the outlook for patients with Gaucher's disease in the developed world such that for most adults, treatment successfully improves the organomegaly and blood counts. However, intravenous therapy is not suitable for all patients. In addition, it is clear that enzyme replacement therapy does not reverse all of the pathology of adult Gaucher's disease. Future challenges include improving therapy, offering patients choice, improving our understanding of the pathophysiology and making treatment available worldwide.