Gaucher disease and therapeutic approaches

Gaucher disease, the most prevalent glycolipid storage disorder, has been treated with Enzyme Replacement Therapy (ERT) using the current gold standard, recombinant imiglucerase (Cerezyme® Genzyme Corporation), for more than 15 years. Based on clinical data from thousands of patients world-wide, it can be said that within 2-5 years, most patients will experience improvement in hemoglobin and platelets, reduction in spleen and liver volumes, improved bone density, and in children in linear growth, as well as reduction in surrogate markers such as chitotriosidase/CCL18 levels. Nonetheless, there are currently unmet clinical goals such as preventing progression of neuronopathic disease, some forms of pulmonary pathology, and skeletal involvement in those at risk for these manifestations. Shire Human Genetics Therapies has recently received FDA approval for ERT with velaglucerase alfa (VPRIV™) and Protalix Pharmaceuticals has successfully completed Phase 3 trials with its plant-derived enzyme, taliglucerase alfa (UPLYSO). Both of these drugs are available via compassionate access programs because of supply shortages of imiglucerase which began mid-2009. Substrate reduction therapy (SRT) with the glucose-analogue, miglustat (Zavesca® Actelion Pharmaceuticals), because of its more problematic safety profile, was approved with a caveat for adults for whom ERT is not appropriate. A ceramide analog SRT (eliglustat; Genzyme Corporation) is currently in clinical trials. Pharmacological chaperones are also currently being tested. Nonetheless, none of these are curative and most symptomatic patients will also require ancillary treatments, most notably, orthopedic surgery.