Gb3/creatinine biomarkers for Fabry disease: Issues to consider

Auray‐Blais, Christiane; Millington, David S.; Barr, Caroline; Young, Sarah P.; Mills, Kevin; Clarke, Joe T.R.

doi:10.1016/j.ymgme.2009.04.006

Cited by 19 publications

(9 citation statements)

References 7 publications

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“…A decrease in u-GL-3 was observed in our subjects and has been advocated as a marker of efficacy in FD, however the clinical relevance remains controversial [13,20]. Some of the controversies stem from a lack of a reliable method for collection of samples and analysis [13,21] . To address these concerns, a new GLP assay for urine GL-3 was developed and validated, and will be used in ongoing migalastat HCl phase 3 studies.…”

Section: Discussionmentioning

confidence: 91%

Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies

Germain

Giugliani

Hughes

et al. 2012

Orphanet Journal of Rare Diseases

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BackgroundFabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day.MethodsTwo open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology.ResultsCompared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients’ increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated.ConclusionsMigalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing.Trial registrationClinicaltrial.gov: NCT00283959 and NCT00283933

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Section: Discussionmentioning

confidence: 91%

Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies

Germain

Giugliani

Hughes

et al. 2012

Orphanet Journal of Rare Diseases

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“…Creatinine concentrations were quantified according to a method of isotope dilution using an ultraperformance liquid chromatography coupled to an electrospray time-of-flight (UPLC-ESI-TOF) mass spectrometry system [30]. The levels of all the urinary biomarkers were expressed as a ratio to creatinine to normalize the concentration of urine [51]. …”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Ferreira

Auray‐Blais

Boutin

et al. 2015

Clinica Chimica Acta

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Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well-characterized subjects carrying several different GLA variant alleles associated with a wide range of residual α-galactosidase A activities. Urinary Gb3 was measured by HPLC–MS/MS; plasma and urinary lyso-Gb3 and related analogs were measured by UPLC–MS/MS. Individual profiles of Gb3 and lyso-Gb3 and related analogs closely correlated with the phenotypic data for each subject, discerning the classical FD patient from the two patients carrying cardiac variants as well as these from all the others without FD. The lyso-Gb3 analog at m/z 836 was found at increased levels only in patients manifesting clinically severe heart disease, irrespective of the pathogenicity of the GLA variant they carried. This finding suggests that this lyso-Gb3 analog might be an earlier biomarker of progressive heart disease, non-specific of the FD cardiomyopathy. The possibility that urinary Gb3 is a specific marker of kidney involvement in FD deserves further study.

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“…In vivo studies on Gb3 synthase knock-out mice, which displayed a total loss of Gb3 and other globo-series GSLs, showed no changes in birthrates and no apparent abnormalities over a year of nurturing, with the exception of total loss of sensitivity to Shiga-like toxins as compared to wild-type mice [76]. On the other hand, elevated levels of Gb3 have been associated with several conditions including Fabry disease [77,78] and a number of cancers [79], such as colon carcinoma [80][81][82], B cell lymphomas [83][84][85][86] and breast cancer [86,87], among others.…”

Section: Globotriaosylceramide (Gb3)mentioning

confidence: 99%

Cell density-induced changes in lipid composition and intracellular trafficking

Kavaliauskiene

Nymark

Bergan

et al. 2013

Cell. Mol. Life Sci.

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Cell density is one of the extrinsic factors to which cells adapt their physiology when grown in culture. However, little is known about the molecular changes which occur during cell growth and how cellular responses are then modulated. In many cases, inhibitors, drugs or growth factors used for in vitro studies change the rate of cell proliferation, resulting in different cell densities in control and treated samples. Therefore, for a comprehensive data analysis, it is essential to understand the implications of cell density on the molecular level. In this study, we have investigated how lipid composition changes during cell growth, and the consequences it has for transport of Shiga toxin. By quantifying 308 individual lipid species from 17 different lipid classes, we have found that the levels and species distribution of several lipids change during cell growth, with the major changes observed for diacylglycerols, phosphatidic acids, cholesterol esters, and lysophosphatidylethanolamines. In addition, there is a reduced binding and retrograde transport of Shiga toxin in high density cells which lead to reduced intoxication by the toxin. In conclusion, our data provide novel information on how lipid composition changes during cell growth in culture, and how these changes can modulate intracellular trafficking.

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Gb3/creatinine biomarkers for Fabry disease: Issues to consider

Cited by 19 publications

References 7 publications

Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies

Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Cell density-induced changes in lipid composition and intracellular trafficking

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