Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice

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 huma...

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Bibliographic Details
Published in:Molecular therapy 2012-04, Vol.20 (4), p.717-726
Main Authors: Benjamin, Elfrida R, Khanna, Richie, Schilling, Adriane, Flanagan, John J, Pellegrino, Lee J, Brignol, Nastry, Lun, Yi, Guillen, Darlene, Ranes, Brian E, Frascella, Michelle, Soska, Rebecca, Feng, Jessie, Dungan, Leo, Young, Brandy, Lockhart, David J, Valenzano, Kenneth J
Format: Article
Language:English
Subjects:
alpha-Galactosidase - therapeutic use
Animals
Blotting, Western
Enzyme Replacement Therapy - methods
Fabry Disease - drug therapy
Fabry Disease - metabolism
Fluorescent Antibody Technique
Humans
Mice
Oligopeptides - therapeutic use
Original
Rats
Recombinant Proteins - therapeutic use
Trihexosylceramides - metabolism
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Summary: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.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2011.271