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

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

Elfrida R Benjamin, Richie Khanna, Adriane Schilling, John J Flanagan, Lee J Pellegrino, Nastry Brignol, Yi Lun, Darlene Guillen, Brian E Ranes, Michelle Frascella, Rebecca Soska, Jessie Feng, Leo Dungan, etc.

Mol Ther. 2012 Apr;20(4):717-26.

PMID: 22215019

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP75172815	Deoxygalactonojirimycin hydrochloride		75172-81-5	Price

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