Figure 1

Conceptual framework for the design of novel therapeutic approaches to Fabry disease: lessons from diabetic nephropathy. A) Pathogenesis of Fabry fibrosis. The traditional view is that this is a late event secondary to endothelial glycolipid deposition leading to luminal obstruction and ischemia. However, fibrosis in other metabolic disorders, such as diabetes, is known to result from recruitment of secondary mediators of injury by both direct actions of accumulated metabolites (in this case glucose) on target organ cells and also by ischemia. Recent evidence suggests that certain metabolites that accumulate in Fabry disease may recruit secondary mediators of injury in target organ cells. Such pathways might be amenable to therapeutic targeting by preventing the effects of accumulated metabolites on target cell or by targeting the secondary mediators that are recruited. B) Potential impact on therapy of an improved understanding of the pathogenesis of fibrosis in Fabry disease. Current therapy of Fabry disease consists of enzyme replacement therapy (ERT). Substrate reduction therapy (SRT) in under investigation and may further decrease the levels of certain metabolites identified as pro-fibrotic. Identification of metabolites recruiting secondary mediators of injury may eventually lead to therapies preventing their binding to receptors. In addition, anti-proteinuric therapy may decrease the pro-inflammatory, pro-fibrotic effects of proteinuria in the kidney. Certain anti-proteinuric agents have additional anti-fibrotic actions in the kidney and vasculature. Finally, targeting of secondary mediators of fibrosis may further prevent fibrosis progression in patients with more advanced disease for whom correction of the initial metabolic defect may not be sufficient.