Objective Deficiency of a-galactosidase A (aGal-A) in Fabry disease leads to the accumulation mainly of globotriaosylceramide (GL3) in multiple renal cell types. Glomerular podocytes are relatively resistant to clearance of GL3 inclusions by enzyme replacement therapy (ERT). Migalastat, an orally bioavailable small molecule capable of chaperoning misfolded αGal-A to lysosomes, is approved in the European Union for the long-term treatment of patients with Fabry disease and amenable GLA (α-galactosidase A enzyme) mutations. We aimed to examine if migalastat reduces GL3 content of podocytes in Fabry disease. Methods and analysis We compared paired renal biopsies of eight adult men with amenable Fabry disease mutations at baseline and after 6 months of treatment with 150 mg migalastat every other day using quantitative unbiased electron microscopic morphometric methods. Results Migalastat treatment led to a reduction in mean total GL3 inclusion volume per podocyte in renal biopsies from baseline to 6 months. This reduction correlated precisely with reduced mean podocyte volume. There was also a direct relationship between reduction in podocyte foot process width and the reduction in mean total podocyte GL3 content following 6 months of migalastat treatment, suggestive of reduced podocyte injury. Conclusion Migalastat treatment of 6 months duration in eight male patients with Fabry disease demonstrated effective GL3 clearance from the podocyte, an important and relatively ERT-resistant glomerular cell.
|Original language||English (US)|
|Number of pages||6|
|Journal||Journal of medical genetics|
|State||Published - Nov 1 2017|
Bibliographical noteFunding Information:
We would like to thank Ms Frida Meiers, Karen Zaruba, Ann Palmer and Zour Yang for their electron microscopy work. We also thank the National Institutes of Health Lysosomal Disease Network (a part of the NCATS Rare Diseases Clinical Research Network (RDCRN)) for providing support (U54NS065768) that led to development of the methodology used in this manuscript for quantification of GL3 inclusions in podocytes. This work was funded by Amicus Corporation.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017.