Enzyme-replacement therapy for metabolic storage disorders

Summary Background After many years of intensive investigation, enzyme-replacement therapy (ERT) has become standard treatment for patients with type 1 (non-neuronopathic) Gaucherʹs disease. ERT has greatly changed the clinical course of this disorder by reducing hepatosplenomegaly, by improving anaemia and thrombocytopenia, and by ameliorating skeletal damage. This example has prompted the investigation of ERT for several other metabolic disorders. The results of several of these trials have recently been published. Recent developments In addition to Gaucherʹs disease, the effects of ERT in four other major metabolic storage disorders have been reported. Among these rare orphan diseases are Fabryʹs disease, in which the heart, kidney, gastrointestinal tract, and peripheral nerves are damaged; Pompeʹs disease, in which the heart, skeletal muscles, and brain are involved; Hurlerʹs disease and Maroteaux-Lamy syndrome in which the eyes, liver, joints, and skeleton are usually affected. Responses to ERT in these four disorders have generally been encouraging although the degree and extent of benefit vary considerably. Where next? There are several critical features of ERT that require attention and amelioration. Among these are the development of severity-score indices that can be used to explicitly quantify the benefit of ERT. The benefit of this treatment has been slight in Fabryʹs disease and is yet to be fully shown in the other three disorders. Secondly, novel technologies need to be developed to deliver therapeutic enzymes effectively to tissues such as the cardiac muscle and kidney in Fabryʹs disease, skeletal muscle in patients with Pompeʹs disease, and to joint tissues and structures in patients with Hurlerʹs disease and Maroteaux-Lamy syndrome. Finally, an all-encompassing concern is to devise methods to ameliorate the damage to the central and peripheral nervous systems that occurs in specific phenotypes of these disorders. In this review we descibe emerging strategies that seem to be useful in these critical regards