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

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dc.contributor.authorYoung-Gqamana, B.
dc.contributor.authorBrignol, N.
dc.contributor.authorChang, H.
dc.contributor.authorKhanna, R.
dc.contributor.authorSoska, R.
dc.contributor.authorFuller, M.
dc.contributor.authorSitaraman, S.
dc.contributor.authorGermain, D.
dc.contributor.authorGiugliani, R.
dc.contributor.authorHughes, D.
dc.contributor.authorMehta, A.
dc.contributor.authorNicholls, K.
dc.contributor.authorBoudes, P.
dc.contributor.authorLockhart, D.
dc.contributor.authorValenzano, K.
dc.contributor.authorBenjamin, E.
dc.contributor.editorSchiffmann, R.
dc.date.issued2013
dc.description.abstractFabry 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.
dc.description.statementofresponsibilityBrandy Young-Gqamana, Nastry Brignol, Hui-Hwa Chang, Richie Khanna, Rebecca Soska, Maria Fuller, Sheela A. Sitaraman, Dominique P. Germain, Roberto Giugliani, Derralynn A. Hughes, Atul Mehta, Kathy Nicholls, Pol Boudes, David J. Lockhart, Kenneth J. Valenzano, Elfrida R. Benjamin
dc.identifier.citationPLoS ONE, 2013; 8(3):e57631-1-e57631-14
dc.identifier.doi10.1371/journal.pone.0057631
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.orcidFuller, M. [0000-0001-9092-8942]
dc.identifier.urihttp://hdl.handle.net/2440/94984
dc.language.isoen
dc.publisherPublic Library of Science
dc.rights© 2013 Young-Gqamana et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pone.0057631
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectFabry Disease
dc.subjectSphingosine
dc.subject1-Deoxynojirimycin
dc.subjectalpha-Galactosidase
dc.subjectGlycolipids
dc.subjectTrihexosylceramides
dc.subjectSphingolipids
dc.subjectAdministration, Oral
dc.subjectReproducibility of Results
dc.subjectMutation
dc.subjectMale
dc.titleMigalastat HCl reduces globotriaosylsphingosine (Lyso-Gb3) in fabry transgenic mice and in the plasma of fabry patients
dc.typeJournal article
pubs.publication-statusPublished

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