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

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 chape...

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Autores principales: Young-Gqamana, Brandy, Brignol, Nastry, Chang, Hui-Hwa, Khanna, Richie, Soska, Rebecca, Fuller, Maria, Sitaraman, Sheela A., Germain, Dominique P., Giugliani, Roberto, Hughes, Derralynn A., Mehta, Atul, Nicholls, Kathy, Boudes, Pol, Lockhart, David J., Valenzano, Kenneth J., Benjamin, Elfrida R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589404/
https://www.ncbi.nlm.nih.gov/pubmed/23472096
http://dx.doi.org/10.1371/journal.pone.0057631
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author Young-Gqamana, Brandy
Brignol, Nastry
Chang, Hui-Hwa
Khanna, Richie
Soska, Rebecca
Fuller, Maria
Sitaraman, Sheela A.
Germain, Dominique P.
Giugliani, Roberto
Hughes, Derralynn A.
Mehta, Atul
Nicholls, Kathy
Boudes, Pol
Lockhart, David J.
Valenzano, Kenneth J.
Benjamin, Elfrida R.
author_facet Young-Gqamana, Brandy
Brignol, Nastry
Chang, Hui-Hwa
Khanna, Richie
Soska, Rebecca
Fuller, Maria
Sitaraman, Sheela A.
Germain, Dominique P.
Giugliani, Roberto
Hughes, Derralynn A.
Mehta, Atul
Nicholls, Kathy
Boudes, Pol
Lockhart, David J.
Valenzano, Kenneth J.
Benjamin, Elfrida R.
author_sort Young-Gqamana, Brandy
collection PubMed
description 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.
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spelling pubmed-35894042013-03-07 Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients Young-Gqamana, Brandy Brignol, Nastry Chang, Hui-Hwa Khanna, Richie Soska, Rebecca Fuller, Maria Sitaraman, Sheela A. Germain, Dominique P. Giugliani, Roberto Hughes, Derralynn A. Mehta, Atul Nicholls, Kathy Boudes, Pol Lockhart, David J. Valenzano, Kenneth J. Benjamin, Elfrida R. PLoS One Research Article 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. Public Library of Science 2013-03-05 /pmc/articles/PMC3589404/ /pubmed/23472096 http://dx.doi.org/10.1371/journal.pone.0057631 Text en © 2013 Young-Gqamana et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Young-Gqamana, Brandy
Brignol, Nastry
Chang, Hui-Hwa
Khanna, Richie
Soska, Rebecca
Fuller, Maria
Sitaraman, Sheela A.
Germain, Dominique P.
Giugliani, Roberto
Hughes, Derralynn A.
Mehta, Atul
Nicholls, Kathy
Boudes, Pol
Lockhart, David J.
Valenzano, Kenneth J.
Benjamin, Elfrida R.
Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients
title Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients
title_full Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients
title_fullStr Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients
title_full_unstemmed Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients
title_short Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients
title_sort migalastat hcl reduces globotriaosylsphingosine (lyso-gb(3)) in fabry transgenic mice and in the plasma of fabry patients
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589404/
https://www.ncbi.nlm.nih.gov/pubmed/23472096
http://dx.doi.org/10.1371/journal.pone.0057631
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