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 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.
Amicus Therapeutics Inc., Cranbury, New Jersey 08512, USA.
Elfrida R
ER
Benjamin
Richie
R
Khanna
Adriane
A
Schilling
John J
JJ
Flanagan
Lee J
LJ
Pellegrino
Nastry
N
Brignol
Yi
Y
Lun
Darlene
D
Guillen
Brian E
BE
Ranes
Michelle
M
Frascella
Rebecca
R
Soska
Jessie
J
Feng
Leo
L
Dungan
Brandy
B
Young
David J
DJ
Lockhart
Kenneth J
KJ
Valenzano
D000818:Animals; D015153:Blotting, Western; D056947:Enzyme Replacement Therapy / Q000379:methods*; D000795:Fabry Disease / Q000188:drug therapy* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000627:therapeutic use*; D051381:Rats; D011994:Recombinant Proteins / Q000627:therapeutic use*; D014281:Trihexosylceramides / Q000378:metabolism; D000519:alpha-Galactosidase / Q000627:therapeutic use*
D009842:Oligopeptides; D011994:Recombinant Proteins; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase; C525167:larazotide acetate