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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb
3
) in Fabry Transgenic Mice and in the Plasma of Fabry Patients
PLoS ONE, Volume 8, No. 3, Article e57631, Year 2013
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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-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. © 2013 Young-Gqamana et al.
Authors & Co-Authors
Young-Gqamana, Brandy
South Africa, Cape Town
University of Cape Town
Brignol, Nastry
United States, Cranbury
Amicus Therapeutics
Chang, Hui Hwa
United States, Cranbury
Amicus Therapeutics
Khanna, Richie
United States, Cranbury
Amicus Therapeutics
Soska, Rebecca
United States, Cranbury
Amicus Therapeutics
Fuller, Maria
Australia, Adelaide
Women's and Children's Hospital Adelaide
Sitaraman, Sheela A.
United States, Cranbury
Amicus Therapeutics
Germain, Dominique P.
France, Versailles
Université de Versailles Saint-quentin-en-yvelines
Giugliani, Roberto
Brazil, Porto Alegre
Universidade Federal do Rio Grande do Sul
Hughes, Derralyn A.
United Kingdom, London
Ucl Medical School
Mehta, Atul B.
United Kingdom, London
Ucl Medical School
Nicholls, Kathleen M.
Australia, Melbourne
Royal Melbourne Hospital
Boudes, Pol
United States, Cranbury
Amicus Therapeutics
Lockhart, David J.
United States, Cranbury
Amicus Therapeutics
Valenzano, Kenneth J.
United States, Cranbury
Amicus Therapeutics
Benjamin, Elfrida R.
United States, Cranbury
Amicus Therapeutics
Statistics
Citations: 40
Authors: 16
Affiliations: 7
Identifiers
Doi:
10.1371/journal.pone.0057631
e-ISSN:
19326203
Research Areas
Genetics And Genomics
Health System And Policy
Participants Gender
Male