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, Brandyen_ZA
dc.contributor.authorBrignol, Nastryen_ZA
dc.contributor.authorChang, Hui-Hwaen_ZA
dc.contributor.authorKhanna, Richieen_ZA
dc.contributor.authorSoska, Rebeccaen_ZA
dc.contributor.authorFuller, Mariaen_ZA
dc.contributor.authorSitaraman, Sheela Aen_ZA
dc.contributor.authorGermain, Dominique Pen_ZA
dc.contributor.authorGiugliani, Robertoen_ZA
dc.contributor.authorHughes, Derralynn Aen_ZA
dc.date.accessioned2015-12-28T06:51:36Z
dc.date.available2015-12-28T06:51:36Z
dc.date.issued2013en_ZA
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-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.en_ZA
dc.identifier.apacitationYoung-Gqamana, B., Brignol, N., Chang, H., Khanna, R., Soska, R., Fuller, M., ... Hughes, D. A. (2013). Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients. <i>PLoS One</i>, http://hdl.handle.net/11427/16066en_ZA
dc.identifier.chicagocitationYoung-Gqamana, Brandy, Nastry Brignol, Hui-Hwa Chang, Richie Khanna, Rebecca Soska, Maria Fuller, Sheela A Sitaraman, Dominique P Germain, Roberto Giugliani, and Derralynn A Hughes "Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients." <i>PLoS One</i> (2013) http://hdl.handle.net/11427/16066en_ZA
dc.identifier.citationYoung-Gqamana, B., Brignol, N., Chang, H. H., Khanna, R., Soska, R., Fuller, M., ... & Benjamin, E. R. (2013). Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients. PloS one, 8(3), e57631. doi:10.1371/journal.pone.0057631en_ZA
dc.identifier.ris TY - Journal Article AU - Young-Gqamana, Brandy AU - Brignol, Nastry AU - Chang, Hui-Hwa AU - Khanna, Richie AU - Soska, Rebecca AU - Fuller, Maria AU - Sitaraman, Sheela A AU - Germain, Dominique P AU - Giugliani, Roberto AU - Hughes, Derralynn A AB - 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. DA - 2013 DB - OpenUCT DO - 10.1371/journal.pone.0057631 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients TI - Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients UR - http://hdl.handle.net/11427/16066 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16066
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0057631
dc.identifier.vancouvercitationYoung-Gqamana B, Brignol N, Chang H, Khanna R, Soska R, Fuller M, et al. Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients. PLoS One. 2013; http://hdl.handle.net/11427/16066.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDivision of Medical Biochemistryen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis 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.en_ZA
dc.rights.holder© 2013 Young-Gqamana et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherBlood plasmaen_ZA
dc.subject.otherMouse modelsen_ZA
dc.subject.otherKidneysen_ZA
dc.subject.otherUrineen_ZA
dc.subject.otherLiquid chromatography-mass spectrometryen_ZA
dc.subject.otherHearten_ZA
dc.subject.otherDrug administrationen_ZA
dc.subject.otherPhase II clinical investigationen_ZA
dc.titleMigalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patientsen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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