Enzyme replacement therapy in Fabry disease: clinical implications

Abstract

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A. The lack of enzyme activity results in an intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide, in various tissues. Significant morbidity is caused by progressive effects on the vascular endothelium, heart, brain and kidney leading to end-stage renal disease. In this review we would like to give a current overview on recent advances in therapy and an outlook on future aspects in the management of Fabry disease. Besides symptomatic management, enzyme replacement therapy with recombinant alpha-galactosidase A is the only specific treatment currently available. Clinical trials using recombinant alpha-galactosidase A showed safety and efficacy in reversing substrate storage in different tissues. Short-term response on clinical manifestations such as impaired kidney function demonstrates a clear potential to improve and stabilize symptoms of the disease. In patients with residual enzyme activity enzyme enhancement therapy with pharmacological chaperones seems to be an attractive approach. Enzyme replacement therapy mediated by gene transfer may become a promising alternative treatment strategy in the future. Remarkable advances in the treatment of patients with Fabry disease have been made with the introduction of enzyme replacement therapy in clinical use. Although lysosomal globotriaosylceramide deposits are cleared very effectively, longer term experience on clinical outcome in patients with severe vital organ involvement is still limited.