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

被引：76

作者：

Benjamin, Elfrida R. ^{[1
]}

Khanna, Richie ^{[1
]}

Schilling, Adriane ^{[1
]}

Flanagan, John J. ^{[1
]}

Pellegrino, Lee J. ^{[1
]}

Brignol, Nastry ^{[1
]}

Lun, Yi ^{[1
]}

Guillen, Darlene ^{[1
]}

Ranes, Brian E. ^{[1
]}

Frascella, Michelle ^{[1
]}

Soska, Rebecca ^{[1
]}

Feng, Jessie ^{[1
]}

Dungan, Leo ^{[1
]}

Young, Brandy ^{[2
]}

Lockhart, David J. ^{[1
]}

Valenzano, Kenneth J. ^{[1
]}

机构：

[1] Amicus Therapeut Inc, Cranbury, NJ 08512 USA

[2] Univ Cape Town, Fac Hlth Sci, ZA-7925 Cape Town, South Africa

来源：

MOLECULAR THERAPY | 2012年 / 20卷 / 04期

关键词：

ENZYME REPLACEMENT THERAPY; AGALSIDASE-BETA THERAPY; LYSOSOMAL STORAGE; DISEASE; GLOBOTRIAOSYLCERAMIDE; 1-DEOXYGALACTONOJIRIMYCIN; STABILIZATION; ACCUMULATION; LYMPHOBLASTS; CORRECTS;

D O I：

10.1038/mt.2011.271

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase alpha-galactosidase A (alpha-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human alpha-Gal A (rh alpha-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rh alpha-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 rh alpha-Gal A via binding and stabilization. AT1001 prevented rh alpha-Gal A denaturation and activity loss in vitro at neutral pH and 37 degrees C. Coincubation of Fabry fibroblasts with rh alpha-Gal A and AT1001 resulted in up to fourfold higher cellular alpha-Gal A and similar to 30% greater GL-3 reduction compared to rh alpha-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rha-Gal A by > 2.5-fold, and in GLA knockout mice resulted in up to fivefold higher alpha-Gal A levels and fourfold greater GL-3 reduction than rh alpha-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rh alpha-Gal A, thus warranting clinical investigation.

引用

页码：717 / 726

页数：10

共 41 条

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[Anonymous], 2006, FABR

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