Co-administration with the pharmacological chaperone AT1001 increases recombinant human α-galactosidase A tissue uptake and improves substrate reduction in Fabry mice

Mol Ther. 2012 Apr;20(4):717-26. doi: 10.1038/mt.2011.271. Epub 2012 Jan 3.


Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase α-galactosidase A (α-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human α-Gal A (rhα-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rhα-Gal A has low physical stability, a short circulating half-life, and variable uptake into different disease-relevant tissues. We hypothesized that coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1-deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rhα-Gal A via binding and stabilization. AT1001 prevented rhα-Gal A denaturation and activity loss in vitro at neutral pH and 37 °C. Coincubation of Fabry fibroblasts with rhα-Gal A and AT1001 resulted in up to fourfold higher cellular α-Gal A and ~30% greater GL-3 reduction compared to rhα-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rhα-Gal A by >2.5-fold, and in GLA knockout mice resulted in up to fivefold higher α-Gal A levels and fourfold greater GL-3 reduction than rhα-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rhα-Gal A, thus warranting clinical investigation.

MeSH terms

  • Animals
  • Blotting, Western
  • Enzyme Replacement Therapy / methods*
  • Fabry Disease / drug therapy*
  • Fabry Disease / metabolism
  • Fluorescent Antibody Technique
  • Humans
  • Mice
  • Oligopeptides / therapeutic use*
  • Rats
  • Recombinant Proteins / therapeutic use*
  • Trihexosylceramides / metabolism
  • alpha-Galactosidase / therapeutic use*


  • Oligopeptides
  • Recombinant Proteins
  • Trihexosylceramides
  • globotriaosylceramide
  • alpha-Galactosidase
  • larazotide acetate