title: The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines.
abstract: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding alpha-galactosidase A (alpha-Gal A), with consequent accumulation of its major glycosphingolipid substrate, globotriaosylceramide (GL-3). Over 500 Fabry mutations have been reported; approximately 60% are missense. The iminosugar 1-deoxygalactonojirimycin (DGJ, migalastat hydrochloride, AT1001) is a pharmacological chaperone that selectively binds alpha-Gal A, increasing physical stability, lysosomal trafficking, and cellular activity. To identify DGJ-responsive mutant forms of alpha-Gal A, the effect of DGJ incubation on alpha-Gal A levels was assessed in cultured lymphoblasts from males with Fabry disease representing 75 different missense mutations, one insertion, and one splice-site mutation. Baseline alpha-Gal A levels ranged from 0 to 52% of normal. Increases in alpha-Gal A levels (1.5- to 28-fold) after continuous DGJ incubation for 5 days were seen for 49 different missense mutant forms with varying EC(50) values (820 nmol/L to >1 mmol/L). Amino acid substitutions in responsive forms were located throughout both structural domains of the enzyme. Half of the missense mutant forms associated with classic (early-onset) Fabry disease and a majority (90%) associated with later-onset Fabry disease were responsive. In cultured fibroblasts from males with Fabry disease, the responses to DGJ were comparable to those of lymphoblasts with the same mutation. Importantly, elevated GL-3 levels in responsive Fabry fibroblasts were reduced after DGJ incubation, indicating that increased mutant alpha-Gal A levels can reduce accumulated substrate. These data indicate that DGJ merits further evaluation as a treatment for patients with Fabry disease with various missense mutations.
authors.affiliation: Amicus Therapeutics, 6 Cedar Brook Drive, Cranbury, NJ 08512, USA. ebenjamin@amicustherapeutics.com
authors.forename: E R
authors.initials: ER
authors.lastname: Benjamin
authors.forename: J J
authors.initials: JJ
authors.lastname: Flanagan
authors.forename: A
authors.initials: A
authors.lastname: Schilling
authors.forename: H H
authors.initials: HH
authors.lastname: Chang
authors.forename: L
authors.initials: L
authors.lastname: Agarwal
authors.forename: E
authors.initials: E
authors.lastname: Katz
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.forename: C
authors.initials: C
authors.lastname: Pine
authors.forename: B
authors.initials: B
authors.lastname: Wustman
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: D J
authors.initials: DJ
authors.lastname: Lockhart
authors.forename: K J
authors.initials: KJ
authors.lastname: Valenzano
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D000795:Fabry Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006207:Half-Life; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000494:pharmacology; D020125:Mutation, Missense / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D000519:alpha-Galactosidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D017485:1-Deoxynojirimycin; C090092:migalastat; D000519:alpha-Galactosidase