204th ENMC International Workshop on Biomarkers in Duchenne Muscular Dystrophy 24–26 January 2014, Naarden, The Netherlands

Ferlini, Alessandra; Flanigan, Kevin M.; Lochmüller, Hanns; Muntoni, F.; Hoen, Peter A.C. ‘t; McNally, Elizabeth M.

doi:10.1016/j.nmd.2014.09.004

Cited by 24 publications

(26 citation statements)

References 50 publications

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“…Duchenne muscular dystrophy (DMD) is a severe muscle‐wasting disease caused by protein truncating mutations in the dystrophin encoding DMD gene . The identification of biomarkers for DMD is a priority to the field to identify prognostic factors and to provide objective readouts to reliably evaluate patients' response to drugs in clinical trials . Several muscle specific molecular entities have been detected in biofluids such as serum, plasma, and urine showing that it is possible to obtain direct muscle‐related information without an invasive muscle biopsy .…”

Section: Introductionmentioning

confidence: 99%

Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies

Spitali

Hettne

Tsonaka

et al. 2018

J cachexia sarcopenia muscle

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BackgroundAnalysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs.MethodsA large‐scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo 31P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross‐sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4 years to allow monitoring of individual disease trajectories based on yearly visits.ResultsCross‐sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over‐representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development.ConclusionsSerum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression.

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Section: Introductionmentioning

confidence: 99%

Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies

Spitali

Hettne

Tsonaka

et al. 2018

J cachexia sarcopenia muscle

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“…Serum CK activity, however, can also be elevated by exercise in non-dystrophic subjects and by a variety of other muscle insults, such as viral infections. As such, elevated serum CK activity is not a specific marker for DMD and elevations can be highly variable even within individual DMD subjects (17, 18). Similarly, increased levels of serum cardiac troponin can be found in DMD patients, who develop dilated cardiomyopathy, but this again can be found in a variety of other cardiac events not specific to DMD(19).…”

Section: Introductionmentioning

confidence: 99%

“…This list suggests that a myriad of molecular changes can arise as muscle damage occurs in DMD patients. Some of these markers are further suggested to have altered expression as muscle pathology and clinical findings progress(17). What is notable about this list, as yet, is that none of the proteins are known to directly interact with dystrophin within the DAG complex, which is why we have undertaken the current study to assay a component of the DAG complex in DMD patient serum.…”

Section: Introductionmentioning

confidence: 99%

N-terminal α Dystroglycan (αDG-N): A Potential Serum Biomarker for Duchenne Muscular Dystrophy

Crowe

Shao

Flanigan

et al. 2016

JND

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Background Duchenne Muscular Dystrophy (DMD) is a severe, progressive, neuromuscular disorder of childhood. While a number of serum factors have been identified as potential biomarkers of DMD, none, as yet, are proteins within the dystrophin-associated glycoprotein (DAG) complex. Objectives We have developed an immobilized serum ELISA assay to measure the expression of a constitutively cleaved and secreted component of the DAG complex, the N-terminal domain of α dystroglycan (αDG-N), and assayed relative expression in serum from muscular dystrophy patients and normal controls. Methods ELISAs of immobilized patient or mouse serum and Western blots were used to assess αDG-N expression. Results Immobilization of diluted serum on ELISA plates was important for this assay, as methods to measure serum αDG-N in solution were less robust. αDG-N ELISA signals were significantly reduced in DMD serum (27±3% decrease, n=9, p<0.001) relative to serum from otherwise normal controls (n=38), and calculated serum αDG-N DMD concentrations were reduced in DMD relative to normal (p<0.01) and Becker Muscular Dystrophy (n=11, p<0.05) patient serum. By contrast, ELISA signals from patients with Inclusion Body Myositis were not different than normal (4±3% decrease, n=8, p=0.99). αDG-N serum signals were also significantly reduced in utrophin-deficient mdx mice as compared to mdx and wild type mice. Conclusions Our results are the first demonstration of a component of the DAG complex as a potential serum biomarker in DMD. Such a serum measure could be further developed as a tool to help reflect overall muscle DAG complex expression or stability.

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“…Indeed, whereas recent development of therapeutic strategies has been extremely rapid, the choice of primary and secondary endpoints has been lagging behind1112. The utility of quantification of the dystrophin itself, as a biomarker, is still under debate.…”

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confidence: 99%

Circulating miRNAs are generic and versatile therapeutic monitoring biomarkers in muscular dystrophies

Israeli¹,

Poupiot²,

Amor³

et al. 2016

Sci Rep

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The development of medical approaches requires preclinical and clinical trials for assessment of therapeutic efficacy. Such evaluation entails the use of biomarkers, which provide information on the response to the therapeutic intervention. One newly-proposed class of biomarkers is the microRNA (miRNA) molecules. In muscular dystrophies (MD), the dysregulation of miRNAs was initially observed in muscle biopsy and later extended to plasma samples, suggesting that they may be of interest as biomarkers. First, we demonstrated that dystromiRs dysregulation occurs in MD with either preserved or disrupted expression of the dystrophin-associated glycoprotein complex, supporting the utilization of dystromiRs as generic biomarkers in MD. Then, we aimed at evaluation of the capacity of miRNAs as monitoring biomarkers for experimental therapeutic approach in MD. To this end, we took advantage of our previously characterized gene therapy approach in a mouse model for α-sarcoglycanopathy. We identified a dose-response correlation between the expression of miRNAs on both muscle tissue and blood serum and the therapeutic benefit as evaluated by a set of new and classically-used evaluation methods. This study supports the utility of profiling circulating miRNAs for the evaluation of therapeutic outcome in medical approaches for MD.

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204th ENMC International Workshop on Biomarkers in Duchenne Muscular Dystrophy 24–26 January 2014, Naarden, The Netherlands

Cited by 24 publications

References 50 publications

Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies

Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies

N-terminal α Dystroglycan (αDG-N): A Potential Serum Biomarker for Duchenne Muscular Dystrophy

Circulating miRNAs are generic and versatile therapeutic monitoring biomarkers in muscular dystrophies

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