title: Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients.
abstract: Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of α-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD.
authors.affiliation: University of Cape Town, Institute of Infectious Disease and Molecular Medicine, Division of Medical Biochemistry, Cape Town, South Africa.
authors.forename: Brandy
authors.initials: B
authors.lastname: Young-Gqamana
authors.forename: Nastry
authors.initials: N
authors.lastname: Brignol
authors.forename: Hui-Hwa
authors.initials: HH
authors.lastname: Chang
authors.forename: Richie
authors.initials: R
authors.lastname: Khanna
authors.forename: Rebecca
authors.initials: R
authors.lastname: Soska
authors.forename: Maria
authors.initials: M
authors.lastname: Fuller
authors.forename: Sheela A
authors.initials: SA
authors.lastname: Sitaraman
authors.forename: Dominique P
authors.initials: DP
authors.lastname: Germain
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.forename: Derralynn A
authors.initials: DA
authors.lastname: Hughes
authors.forename: Atul
authors.initials: A
authors.lastname: Mehta
authors.forename: Kathy
authors.initials: K
authors.lastname: Nicholls
authors.forename: Pol
authors.initials: P
authors.lastname: Boudes
authors.forename: David J
authors.initials: DJ
authors.lastname: Lockhart
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Valenzano
authors.forename: Elfrida R
authors.initials: ER
authors.lastname: Benjamin
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000795:Fabry Disease / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D006017:Glycolipids / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D015203:Reproducibility of Results; D013107:Sphingolipids / Q000097:blood / Q000378:metabolism*; D013110:Sphingosine / Q000378:metabolism*; D014281:Trihexosylceramides / Q000097:blood / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000235:genetics
chemical_list: D006017:Glycolipids; D013107:Sphingolipids; D014281:Trihexosylceramides; C063288:globotriaosyl lysosphingolipid; D017485:1-Deoxynojirimycin; C018549:globotriaosylceramide; C090092:migalastat; D000519:alpha-Galactosidase; D013110:Sphingosine