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

PLoS One. 2013;8(3):e57631. doi: 10.1371/journal.pone.0057631. Epub 2013 Mar 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / pharmacology
  • Administration, Oral
  • Animals
  • Fabry Disease / blood
  • Fabry Disease / drug therapy
  • Fabry Disease / genetics*
  • Glycolipids / blood
  • Glycolipids / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Reproducibility of Results
  • Sphingolipids / blood
  • Sphingolipids / metabolism*
  • Sphingosine / metabolism*
  • Trihexosylceramides / blood
  • Trihexosylceramides / metabolism*
  • alpha-Galactosidase / genetics

Substances

  • Glycolipids
  • Sphingolipids
  • Trihexosylceramides
  • globotriaosyl lysosphingolipid
  • 1-Deoxynojirimycin
  • globotriaosylceramide
  • migalastat
  • alpha-Galactosidase
  • Sphingosine

Grants and funding

Amicus Therapeutics funded the research and the publication fees. Amicus Therapeutics designed and performed the study, collected and analyzed the data, made the decision to publish, and prepared the manuscript. No external funding was used for this study.