Back to Search Start Over

Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice

Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice

Authors :
Kate Chang
Amol Ketkar
Nicola Robertson
Masahito Miyamoto
Kenneth J. Valenzano
Yi Lun
Nastry Brignol
Su Xu
Kazutoshi Mihara
Rebecca Soska
Jessie Feng
Hidehito Yasukawa
Robert Boyd
Michelle Frascella
Carole Shardlow
Rick Hamler
Susie Fowles
Alison Churchill
Richie Khanna
David J. Lockhart
Anadina Garcia
Tohru Hirato
Elfrida R. Benjamin
Adriane Schilling
Sean Sullivan
Source :
Molecular Therapy
Publication Year :
2015
Publisher :
Elsevier BV, 2015.

Abstract

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene that encodes α-galactosidase A and is characterized by pathological accumulation of globotriaosylceramide and globotriaosylsphingosine. Earlier, the authors demonstrated that oral coadministration of the pharmacological chaperone AT1001 (migalastat HCl; 1-deoxygalactonojirimycin HCl) prior to intravenous administration of enzyme replacement therapy improved the pharmacological properties of the enzyme. In this study, the authors investigated the effects of coformulating AT1001 with a proprietary recombinant human α-galactosidase A (ATB100) into a single intravenous formulation. AT1001 increased the physical stability and reduced aggregation of ATB100 at neutral pH in vitro, and increased the potency for ATB100-mediated globotriaosylceramide reduction in cultured Fabry fibroblasts. In Fabry mice, AT1001 coformulation increased the total exposure of active enzyme, and increased ATB100 levels in cardiomyocytes, cardiac vascular endothelial cells, renal distal tubular epithelial cells, and glomerular cells, cell types that do not show substantial uptake with enzyme replacement therapy alone. Notably, AT1001 coformulation also leads to greater tissue globotriaosylceramide reduction when compared with ATB100 alone, which was positively correlated with reductions in plasma globotriaosylsphingosine. Collectively, these data indicate that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation.

Details

ISSN :
15250016
Volume :
23
Issue :
7
Database :
OpenAIRE
Journal :
Molecular Therapy
Accession number :
edsair.doi.dedup.....5db797d492b47f1734acc9db7156d0d8
Full Text :
https://doi.org/10.1038/mt.2015.87