Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients

Young-Gqamana, Brandy; Brignol, Nastry; Chang, Hui-Hwa; Khanna, Richie; Soska, Rebecca; Fuller, Maria; Sitaraman, Sheela A; Germain, Dominique P; Giugliani, Roberto; Hughes, Derralynn A

Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients

Journal Article

2013

Journal Title

PLoS One

Link to Journal

http://journals.plos.org/plosone

Publisher

Public Library of Science

Publisher

University of Cape Town

Department

Division of Medical Biochemistry

Faculty

Faculty of Health Sciences

License

http://creativecommons.org/licenses/by/4.0

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-Gb 3 ). 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-Gb 3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb 3 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-Gb 3 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-Gb 3 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-Gb 3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD.