Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy
Abstract Background Duchenne muscular dystrophy (DMD) is a fatal disease for which no cure is available. Clinical trials have shown to be largely underpowered due to inter‐individual variability and noisy outcome measures. The availability of biomarkers able to anticipate clinical benefit is highly...
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Wiley
2020-04-01
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Series: | Journal of Cachexia, Sarcopenia and Muscle |
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Online Access: | https://doi.org/10.1002/jcsm.12517 |
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doaj-279f86f1eb524b11a1cf2dcdaf841012 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mirko Signorelli Burcu Ayoglu Camilla Johansson Hanns Lochmüller Volker Straub Francesco Muntoni Erik Niks Roula Tsonaka Anja Persson Annemieke Aartsma‐Rus Peter Nilsson Cristina Al‐Khalili Szigyarto Pietro Spitali |
spellingShingle |
Mirko Signorelli Burcu Ayoglu Camilla Johansson Hanns Lochmüller Volker Straub Francesco Muntoni Erik Niks Roula Tsonaka Anja Persson Annemieke Aartsma‐Rus Peter Nilsson Cristina Al‐Khalili Szigyarto Pietro Spitali Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy Journal of Cachexia, Sarcopenia and Muscle Duchenne muscular dystrophy Protein biomarkers Prognostic biomarker Rare diseases Serum biomarkers |
author_facet |
Mirko Signorelli Burcu Ayoglu Camilla Johansson Hanns Lochmüller Volker Straub Francesco Muntoni Erik Niks Roula Tsonaka Anja Persson Annemieke Aartsma‐Rus Peter Nilsson Cristina Al‐Khalili Szigyarto Pietro Spitali |
author_sort |
Mirko Signorelli |
title |
Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy |
title_short |
Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy |
title_full |
Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy |
title_fullStr |
Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy |
title_full_unstemmed |
Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy |
title_sort |
longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for duchenne muscular dystrophy |
publisher |
Wiley |
series |
Journal of Cachexia, Sarcopenia and Muscle |
issn |
2190-5991 2190-6009 |
publishDate |
2020-04-01 |
description |
Abstract Background Duchenne muscular dystrophy (DMD) is a fatal disease for which no cure is available. Clinical trials have shown to be largely underpowered due to inter‐individual variability and noisy outcome measures. The availability of biomarkers able to anticipate clinical benefit is highly needed to improve clinical trial design and facilitate drug development. Methods In this study, we aimed to appraise the value of protein biomarkers to predict prognosis and monitor disease progression or treatment outcome in patients affected by DMD. We collected clinical data and 303 blood samples from 157 DMD patients in three clinical centres; 78 patients contributed multiple blood samples over time, with a median follow‐up time of 2 years. We employed linear mixed models to identify biomarkers that are associated with disease progression, wheelchair dependency, and treatment with corticosteroids and performed survival analysis to find biomarkers whose levels are associated with time to loss of ambulation. Results Our analysis led to the identification of 21 proteins whose levels significantly decrease with age and nine proteins whose levels significantly increase. Seven of these proteins are also differentially expressed in non‐ambulant patients, and three proteins are differentially expressed in patients treated with glucocorticosteroids. Treatment with corticosteroids was found to partly counteract the effect of disease progression on two biomarkers, namely, malate dehydrogenase 2 (MDH2, P = 0.0003) and ankyrin repeat domain 2 (P = 0.0005); however, patients treated with corticosteroids experienced a further reduction on collagen 1 serum levels (P = 0.0003), especially following administration of deflazacort. A time to event analysis allowed to further support the use of MDH2 as a prognostic biomarker as it was associated with an increased risk of wheelchair dependence (P = 0.0003). The obtained data support the prospective evaluation of the identified biomarkers in natural history and clinical trials as exploratory biomarkers. Conclusions We identified a number of serum biomarkers associated with disease progression, loss of ambulation, and treatment with corticosteroids. The identified biomarkers are promising candidate prognostic and surrogate biomarkers, which may support drug developers if confirmed in prospective studies. The serum levels of MDH2 are of particular interest, as they correlate with disease stage and response to treatment with corticosteroids, and are also associated with the risk of wheelchair dependency and pulmonary function. |
topic |
Duchenne muscular dystrophy Protein biomarkers Prognostic biomarker Rare diseases Serum biomarkers |
url |
https://doi.org/10.1002/jcsm.12517 |
work_keys_str_mv |
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doaj-279f86f1eb524b11a1cf2dcdaf8410122020-11-25T03:21:25ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092020-04-0111250551710.1002/jcsm.12517Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophyMirko Signorelli0Burcu Ayoglu1Camilla Johansson2Hanns Lochmüller3Volker Straub4Francesco Muntoni5Erik Niks6Roula Tsonaka7Anja Persson8Annemieke Aartsma‐Rus9Peter Nilsson10Cristina Al‐Khalili Szigyarto11Pietro Spitali12Department of Biomedical Data Sciences Leiden University Medical Center Leiden The NetherlandsDepartment of Protein Sciences, SciLifeLab, School of Engineering Sciences in Chemistry, Biotechnology and Health KTH Royal Institute of Technology Stockholm SwedenDepartment of Protein Science, School of Chemistry, Biotechnology and Health KTH Royal Institute of Technology Stockholm SwedenDepartment of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center University of Freiburg Freiburg GermanyMRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine Newcastle University Newcastle upon Tyne UKThe Dubowitz Neuromuscular Centre UCL Institute of Child Health London UKDepartment of Neurology Leiden University Medical Center Leiden The NetherlandsDepartment of Biomedical Data Sciences Leiden University Medical Center Leiden The NetherlandsDepartment of Protein Science, School of Chemistry, Biotechnology and Health KTH Royal Institute of Technology Stockholm SwedenChildren's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa CanadaDivision of Affinity Proteomics, SciLifeLab, Department of Protein Science KTH Royal Institute of Technology Stockholm SwedenDepartment of Protein Sciences, SciLifeLab, School of Engineering Sciences in Chemistry, Biotechnology and Health KTH Royal Institute of Technology Stockholm SwedenDepartment of Human Genetics Leiden University Medical Center Leiden The NetherlandsAbstract Background Duchenne muscular dystrophy (DMD) is a fatal disease for which no cure is available. Clinical trials have shown to be largely underpowered due to inter‐individual variability and noisy outcome measures. The availability of biomarkers able to anticipate clinical benefit is highly needed to improve clinical trial design and facilitate drug development. Methods In this study, we aimed to appraise the value of protein biomarkers to predict prognosis and monitor disease progression or treatment outcome in patients affected by DMD. We collected clinical data and 303 blood samples from 157 DMD patients in three clinical centres; 78 patients contributed multiple blood samples over time, with a median follow‐up time of 2 years. We employed linear mixed models to identify biomarkers that are associated with disease progression, wheelchair dependency, and treatment with corticosteroids and performed survival analysis to find biomarkers whose levels are associated with time to loss of ambulation. Results Our analysis led to the identification of 21 proteins whose levels significantly decrease with age and nine proteins whose levels significantly increase. Seven of these proteins are also differentially expressed in non‐ambulant patients, and three proteins are differentially expressed in patients treated with glucocorticosteroids. Treatment with corticosteroids was found to partly counteract the effect of disease progression on two biomarkers, namely, malate dehydrogenase 2 (MDH2, P = 0.0003) and ankyrin repeat domain 2 (P = 0.0005); however, patients treated with corticosteroids experienced a further reduction on collagen 1 serum levels (P = 0.0003), especially following administration of deflazacort. A time to event analysis allowed to further support the use of MDH2 as a prognostic biomarker as it was associated with an increased risk of wheelchair dependence (P = 0.0003). The obtained data support the prospective evaluation of the identified biomarkers in natural history and clinical trials as exploratory biomarkers. Conclusions We identified a number of serum biomarkers associated with disease progression, loss of ambulation, and treatment with corticosteroids. The identified biomarkers are promising candidate prognostic and surrogate biomarkers, which may support drug developers if confirmed in prospective studies. The serum levels of MDH2 are of particular interest, as they correlate with disease stage and response to treatment with corticosteroids, and are also associated with the risk of wheelchair dependency and pulmonary function.https://doi.org/10.1002/jcsm.12517Duchenne muscular dystrophyProtein biomarkersPrognostic biomarkerRare diseasesSerum biomarkers |