α-L-Iduronidase and enzyme replacement therapy for mucopolysaccharidosis I

Abstract

Mucopolysaccharidosis I (McKusick 25280, Hurler syndrome, Scheie syndrome) is caused by a deficiency in the lysosomal hydrolase, α-L-iduronidase (EC 3.2.1.76) and results in a failure to degrade the glycosaminoglycans, dermatan sulfate and heparan sulfate. Mucopolysaccharidosis I patients present within a spectrum of clinical phenotypes, where Hurler and Scheie syndromes represent the two extremes. In the 80 or more years since the discovery of mucopolysaccharidosis I, the molecular defect has been defined, the α-L-iduronidase protein purified and characterised, the α-L-iduronidase (IDUA) gene cloned, molecular genetic studies performed and expression systems developed. These advances have allowed the development of α-L-iduronidase enzyme replacement therapy as a treatment strategy for mucopolysaccharidosis I patients. Using animal models of mucopolysaccharidosis I, the efficacy of α-L-iduronidase replacement therapy has been evaluated and justified the initiation of human clinical trials in mucopolysaccharidosis I patients. Phase I/II and Phase III clinical trials have recently been conducted and demonstrated that this therapy is effective in treating patients with the attenuated forms of mucopolysaccharidosis I (that is, little or no neuronal involvement). Further development of this technology is required to effectively treat the problem sites of neuronal and skeletal pathology, present in severe Hurler syndrome patients.