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Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients.
- Source :
-
PloS one [PLoS One] 2013; Vol. 8 (3), pp. e57631. Date of Electronic Publication: 2013 Mar 05. - Publication Year :
- 2013
-
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.
- Subjects :
- 1-Deoxynojirimycin pharmacology
Administration, Oral
Animals
Fabry Disease blood
Fabry Disease drug therapy
Glycolipids blood
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Reproducibility of Results
Sphingolipids blood
Trihexosylceramides blood
alpha-Galactosidase genetics
1-Deoxynojirimycin analogs & derivatives
Fabry Disease genetics
Glycolipids metabolism
Sphingolipids metabolism
Sphingosine metabolism
Trihexosylceramides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23472096
- Full Text :
- https://doi.org/10.1371/journal.pone.0057631