Cross‐sectional serum metabolomic study of multiple forms of muscular dystrophy

Spitali, Pietro; Hettne, Kristina; Tsonaka, Roula; Sabir, Ekrem; Seyer, Alexandre; Hemerik, Jesse; Goeman, Jelle J.; Picillo, Esther; Ergoli, Manuela; Politano, Luisa; Aartsma‐Rus, Annemieke

doi:10.1111/jcmm.13543

Cited by 25 publications

(31 citation statements)

References 35 publications

(59 reference statements)

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“…Major advances have occurred in the past few years in the discovery of serum molecular biomarkers in patients affected with Duchenne muscular dystrophy (DMD). These include blood circulating proteins 1–3 , circulating miRNA 4–6 and circulating metabolites 7,8 . Several of these biomarkers were confirmed using independent DMD cohorts and across different laboratories, and in animal models such as mdx mouse 9,10 and golden retriever muscular dystrophy dog 11,12 , further confirming the association of these molecular biomarkers with dystrophin deficiency and dystrophic muscle pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy

Hathout

Chen

Ogundele

et al. 2019

Sci Rep

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Extensive biomarker discoveries for DMD have occurred in the past 7 years, and a vast array of these biomarkers were confirmed in independent cohorts and across different laboratories. In these previous studies, glucocorticoids and age were two major confounding variables. In this new study, using SomaScan technology and focusing on a subset of young DMD patients who were not yet treated with glucocorticoids, we identified 108 elevated and 70 decreased proteins in DMD relative to age matched healthy controls (p value < 0.05 after adjusting for multiple testing). The majority of the elevated proteins were muscle centric followed by cell adhesion, extracellular matrix proteins and a few pro-inflammatory proteins. The majority of decreased proteins were of cell adhesion, however, some had to do with cell differentiation and growth factors. Subsequent treatment of this group of DMD patients with glucocorticoids affected two major groups of pharmacodynamic biomarkers. The first group consisted of 80 serum proteins that were not associated with DMD and either decreased or increased following treatment with glucocorticoids, and therefore were reflective of a broader effect of glucocorticoids. The second group consisted of 17 serum proteins that were associated with DMD and these tended to normalize under treatment, thus reflecting physiologic effects of glucocorticoid treatment in DMD. In summary, we have identified a variety of circulating protein biomarkers that reflect the complex nature of DMD pathogenesis and response to glucocorticoids.

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Section: Introductionmentioning

confidence: 99%

Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy

Hathout

Chen

Ogundele

et al. 2019

Sci Rep

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“…This type of biomarkers would enable drug developers to reduce the costs of clinical trials, while reducing the unnecessary exposure of patients to biological drugs, which often come with complicated patient management and increase risk of safety issues compared with conventional drugs. Biomarker research is ranging from MRI/MRS to blood/urine based biomarkers in order to maximize the information for the whole body while reducing the need of resorting to invasive procedures such as obtaining muscle biopsies.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy

Signorelli

Ayoglu

Johansson

et al. 2019

J cachexia sarcopenia muscle

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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.

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“…arginine, glutamine, and histidine [43] as well as metabolites eg. creatine has been identified as potential biomarker candidates [44,45]. Additional studies of miRNA and metabolites in longitudinally collected samples can provide essential evidence to promote their use as blood biomarkers in a clinical setup [46].…”

Section: Protein Biomarkers For Dmdmentioning

confidence: 99%

Duchenne Muscular Dystrophy: recent advances in protein biomarkers and the clinical application

Szigyarto

2020

Expert Review of Proteomics

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Introduction: Early biomarker discovery studies have praised the value of their emerging results, predicting an unprecedented impact on health care. Biomarkers are expected to provide tests with increased specificity and sensitivity compared to existing measures, improve the decision-making process, and accelerate the development of therapies. For rare disorders, like Duchenne Muscular Dystrophy (DMD) such biomarkers can assist the development of therapies, therefore also helping to find a cure for the disease. Area covered: State-of-the-art technologies have been used to identify blood biomarkers for DMD and efforts have been coordinated to develop and promote translation of biomarkers for clinical practice. Biomarker translation to clinical practice is however, adjoined by challenges related to the complexity of the disease, involving numerous biological processes, and the limited sample resources. This review highlights the current progress on the development of biomarkers, describing the proteomics technologies used, the most promising findings and the challenges encountered. Expert opinion: Strategies for effective use of samples combined with orthogonal proteomics methods for protein quantification are essential for translating biomarkers to the patient's bed side. Progress is achieved only if strong evidence is provided that the biomarker constitutes a reliable indicator of the patient's health status for a specific context of use.

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Cross‐sectional serum metabolomic study of multiple forms of muscular dystrophy

Cited by 25 publications

References 35 publications

Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy

Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy

Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy

Duchenne Muscular Dystrophy: recent advances in protein biomarkers and the clinical application

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