Plasma globotriaosylsphingosine as a biomarker of Fabry disease

Togawa, Tadayasu; Kodama, Takashi; Suzuki, Toshihiro; Sugawara, Kazuki; Tsukimura, Takahiro; Ohashi, Toya; Ishige, Nobuyuki; Suzuki, K.; Kitagawa, Teruo; Sakuraba, Hitoshi

doi:10.1016/j.ymgme.2010.03.020

Cited by 131 publications

(133 citation statements)

References 24 publications

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“…Finally, although some studies support globotriaosylsphingosine as a potentially useful biomarker for monitoring Fabry disease, this evidence has been generated in relatively recent years. 6,21,22 At the time of the design of the clinical trials included in the current report, globotriaosylsphingosine was not considered a potential surrogate marker of Fabry disease progression or response to treatment and, thus, was not included as a measured end point. The biological reason why changes in plasma or urine Gb 3 concentrations are not useful as biomarkers is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4] Plasma Gb 3 concentration has been found to be consistently elevated in hemizygous males with classic Fabry disease but variably elevated in some variant hemizygous males with residual enzyme activity and in heterozygous females. 5,6 No evidence has been published supporting the use of plasma or urine Gb 3 concentrations as a biomarker for disease progression or response to treatment. For patients with elevated plasma or urine Gb 3 concentrations before treatment, enzyme replacement therapy (ERT) results in an initial drop in Gb 3 concentrations.…”

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confidence: 99%

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Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

Schiffmann¹,

Ries

Blankenship

et al. 2013

Genetics in Medicine

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Original research articleGlobotriaosylceramide (Gb 3 ) is often elevated in the urine of patients with Fabry disease, 1 and some studies support its use as a diagnostic biomarker. [2][3][4] Plasma Gb 3 concentration has been found to be consistently elevated in hemizygous males with classic Fabry disease but variably elevated in some variant hemizygous males with residual enzyme activity and in heterozygous females. 5,6 No evidence has been published supporting the use of plasma or urine Gb 3 concentrations as a biomarker for disease progression or response to treatment. For patients with elevated plasma or urine Gb 3 concentrations before treatment, enzyme replacement therapy (ERT) results in an initial drop in Gb 3 concentrations. 5,7 The lower Gb 3 concentrations do not remain low in all patients and do not always coincide with clinical improvement. 8 Biomarkers are generally defined as measurements that reflect the activity of a disease process 9 and can be (i) prognostic, (ii) predictive, or (iii) pharmacodynamic. 10 The goal of this study was to assess the relationship of plasma and urine Gb 3 concentrations with renal or cardiac outcome measures. A previous analysis of pooled data from three randomized, placebo-controlled clinical trials and their open-label extensions (sponsored by Shire Human Genetic Therapies) of male patients with Fabry disease suggested a stabilizing effect of agalsidase alfa (agalα) on renal function assessed by measured glomerular filtration rate (GFR). 11 In that analysis, baseline GFR or elevated proteinuria category (≥1 g/24 h) significantly predicted GFR decline during treatment. Using a suitable selection approach of pooled data Purpose: Globotriaosylceramide concentrations were assessed as potential predictors of change from baseline after 12 months by estimated glomerular filtration rate and left-ventricular mass index using pooled data from three randomized, placebo-controlled agalsidase alfa trials and open-label extensions of patients with Fabry disease.Methods: Males (aged 18 years or older) with Fabry disease received agalsidase alfa (0.2 mg/kg every other week for 12 months). A backward-elimination approach evaluated potential predictors (baseline estimated glomerular filtration rate and left-ventricular mass index; age at first dose; baseline and change from baseline at 12 months of globotriaosylceramide (urine, plasma); urine protein excretion; and systolic and diastolic blood pressure). Subgroups included patients randomized to placebo or agalsidase alfa (double-blind phase), then to agalsidase alfa (open-label extensions; placebo→agalsidase alfa or agalsidase alfa→agalsidase alfa, respectively) and stage 2/3 chronic kidney disease patients.Results: Baseline estimated glomerular filtration rate, age at first dose, baseline urine globotriaosylceramide excretion, and baseline and change from baseline urine protein excretion significantly predicted change from baseline estimated glomerular filtration rate in the analysis population (N = 73; all P<0.05), although not in...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

Schiffmann¹,

Ries

Blankenship

et al. 2013

Genetics in Medicine

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“…Recently, lyso-GL-3 has emerged as a more sensitive biomarker that may correlate with disease severity and/or organ involvement in FD (Rombach et al 2010). Untreated patients with classic FD typically have highly elevated plasma levels of lyso-GL-3 (Aerts et al 2008;Togawa et al 2010;Niemann et al 2014), and plasma lyso-GL-3 decreased within 3 months of initiation of treatment in naive FD patients treated with either agalsidase alfa or agalsidase beta, with significantly larger reductions with agalsidase beta 1.0 mg/kg versus agalsidase alfa and agalsidase beta 0.2 mg/kg (van Breemen et al 2011). Recurrent elevations in plasma lyso-GL-3 have been reported in patients whose agalsidase dose was reduced.…”

Section: Introductionmentioning

confidence: 99%

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Göker-Alpan

Gambello

Maegawa³

et al. 2015

JIMD Reports

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Introduction: Agalsidase alfa and agalsidase beta, recombinant enzyme preparations for treatment of Fabry disease (FD), have different approved dosing schedules: 0.2 mg/kg and 1.0 mg/kg every other week (EOW), respectively.Methods: This open-label, multicenter, exploratory phase 4 study evaluated plasma globotriaosylsphingosine (lyso-GL-3) and plasma and urine globotriaosylceramide (GL-3) levels at baseline and 2, 4, and 6 months after the switch from agalsidase alfa (0.2 mg/kg EOW for !12 months) to agalsidase beta (1.0 mg/kg EOW) in 15 male patients with FD. Immunoglobulin (Ig)G antidrug antibody titers were assessed, and safety was monitored throughout the study.Results: Plasma lyso-GL-3 concentrations decreased significantly within 2 months after switch and reductions continued through month 6 (mean absolute changes, À12.8, À16.1, and À16.7 ng/mL at 2, 4, and 6 months, respectively; all P < 0.001). The mean percentage reduction from baseline was 39.5% (P < 0.001) at month 6. For plasma GL-3, the mean absolute change from baseline (À0.9 mg/mL) and percentage reduction (17.9%) at month 6 were both significant (P < 0.05). Urine GL-3 measurements showed intra-patient variability and changes from baseline were not significant. No clinical outcomes were assessed in this 6-month study, and, therefore, no conclusions can be drawn regarding the correlation of observed reductions in glycosphingolipid concentrations with clinically relevant outcomes. There were no differences in IgG antidrug antibody titers between the two enzymes. The switch from agalsidase alfa to agalsidase beta was well tolerated.Conclusion: Plasma lyso-GL-3 and GL-3 levels reduced after switching from agalsidase alfa to agalsidase beta, indicating that agalsidase beta has a greater pharmacodynamic effect on these markers at the recommended dose. These data further support the use of agalsidase beta 1.0 mg/kg EOW as enzyme replacement therapy in FD.

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“…[3][4][5] Recently, researcher have paid attention to the excretion of plasma lyso-Gb3 level and published it's significant correlation with clinical severity of disease manifestations. 6,7,[9][10][11] Traditionally analytical method of lyso-Gb3 was based on O-phthalaldehyde derivatization of amine in the lysoglycolipid followed by HPLC-fluorescence detection. 11-14 LC-MS/MS has it's own strengths such as high sensitivity, specificity and rapidity of analysis, thus the paradigm of the analysis is getting shifted to the usage of LC-MS/MS including lyso-Gb3.…”

Section: Introductionmentioning

confidence: 99%

A Fast Determination of Globotriaosylsphingosine in Plasma for Screening Fabry Disease Using UPLC-ESI-MS/MS

Yoon¹

2015

Mass Spectrometry Letters

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: Globotriaosylsphingosine (lyso-Gb3) is considered as one of the biological marker for Fabry disease. To date, a reliable biomarker that reflects disease severity and progression has not been discovered to guide the management of Fabry disease. A new method included a simple protein precipitation with acetonitrile in 100 µL of plasma following analyte separation on an Phenomenex Kintex-C18 column using a gradient elution (0.1% formic acid in 5-90% acetonitrile). Total run time was within 12 min including sample preparation and MS/MS analysis. The limit of detection and limit of quantitation were 1 ng/mL and 2 ng/mL, respectively. The calibration curve was linear over the concentration range of 2.0-200.0 ng/mL (r 2 = 0.9999). Inter-day accuracy and precision at 7 level were 93.4-100.7% with RSD of 0.55-5.97%. Absolute recovery was 97.6-98.6%. The method was applied to human and mice plasma, proved the suitability for quantification of lyso-Gb3 for screening, diagnosis and therapeutic monitoring of Fabry disease patients.

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Plasma globotriaosylsphingosine as a biomarker of Fabry disease

Cited by 131 publications

References 24 publications

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

A Fast Determination of Globotriaosylsphingosine in Plasma for Screening Fabry Disease Using UPLC-ESI-MS/MS

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