Novel therapeutic targets for the treatment of Fabry disease.

摘要

Fabry disease is an X-linked lysosomal storage disorder resulting from deficient activity of alpha-galactosidase A. The traditional concept that is used to explain the complications of the disease involves progressive accumulation of globotriaosylceramide in endothelial and smooth muscle cells, resulting in vascular damage. Clinically, progressive renal insufficiency, cardiac involvement and brain pathology evolves. Two pharmaceutical companies have developed enzyme replacement therapy in Fabry disease. Although the first clinical trials showed great promise, it is clear that long-term effects are not as robust as was anticipated. Stabilisation of renal function and decreases in cardiac hypertrophy has been observed, but some patients may experience progressive complications. As there are recent indications that serum components contribute to the pathophysiology of Fabry disease, fundamental studies are needed to unravel the precise role and identity of these factors. Combination of these basic studieswith clinical follow up may ultimately reveal when the 'point of no return' is reached. Advanced renal insufficiency seems to be a clinical indicator of lack of response, but other signs and symptoms are probably related to adverse outcome. It is anticipated that in the future controlled studies in early symptomatic or presymptomatic patients will be required. In addition, alternative strategies such as substrate reduction or chaperone therapy, either alone or in combination with enzyme replacement therapy, should be explored. Because Fabry disease is rare, collaborative efforts should be undertaken and openness of data should be strived for.