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Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients

Young-Gqamana, B; Brignol, N; Chang, H-H; Khanna, R; Soska, R; Fuller, M; Sitaraman, SA; ... Benjamin, ER; + view all (2013) Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients. PLOS ONE , 8 (3) , Article e57631. 10.1371/journal.pone.0057631. Green open access

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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.

Type: Article
Title: Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0057631
Publisher version: http://dx.doi.org/10.1371/journal.pone.0057631
Language: English
Additional information: © 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. 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. Competing interests: Brandy Young-Gqamana is a former employee of Amicus Therapeutics. Nastry Brignol, Hui-Hwa Chang, Richie Khanna, Rebecca Soska, Sheela A. Sitaraman, Pol Boudes, David J. Lockhart, Kenneth J. Valenzano, and Elfrida R. Benjamin are employed by Amicus Therapeutics and are shareholders in the company. Maria Fuller was a collaborator with Amicus Therapeutics. All other authors were investigators on the Phase 2 clinical studies of migalastat HCl. Dominique P. Germain has received research funding, consultancy fees, and travel expenses from Genzyme and Shire HGT. Roberto Giugliani is a consultant and investigator for Actelion, Amicus, BioMarin, Genzyme and Shire HGT. Derralynn A. Hughes is a consultant for Amicus, Shire HGT, Genzyme, Actelion, has been on a Speaker's Bureau for Amicus, Shire HGT, Genzyme, and Actelion, and has received grants from Amicus, Shire HGT, and Genzyme. Atul Mehta has received honoraria, research funding, consultancy fees, and travel expenses from Shire HGT, Genzyme, Actelion, Protalix, and Amicus. Kathy Nicholls has received travel and research support and speaker's honoraria from Amicus, Shire HGT and Genzyme. Amicus Therapeutics funded the research and any publication fees. The α-Gal A (Fabrazyme) used in this study is a product produced by Genzyme. Maria Fuller is employed by SA Pathology, Adelaide. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all of the PLOS ONE policies on sharing data and materials.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/1391151
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