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Discovery of Metabolic Biomarkers for Duchenne Muscular Dystrophy within a Natural History Study.

ABSTRACT: Serum metabolite profiling in Duchenne muscular dystrophy (DMD) may enable discovery of valuable molecular markers for disease progression and treatment response. Serum samples from 51 DMD patients from a natural history study and 22 age-matched healthy volunteers were profiled using liquid chromatography coupled to mass spectrometry (LC-MS) for discovery of novel circulating serum metabolites associated with DMD. Fourteen metabolites were found significantly altered (1% false discovery rate) in their levels between DMD patients and healthy controls while adjusting for age and study site and allowing for an interaction between disease status and age. Increased metabolites included arginine, creatine and unknown compounds at m/z of 357 and 312 while decreased metabolites included creatinine, androgen derivatives and other unknown yet to be identified compounds. Furthermore, the creatine to creatinine ratio is significantly associated with disease progression in DMD patients. This ratio sharply increased with age in DMD patients while it decreased with age in healthy controls. Overall, this study yielded promising metabolic signatures that could prove useful to monitor DMD disease progression and response to therapies in the future.

SUBMITTER: Boca SM

PROVIDER: S-EPMC4833348 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Discovery of Metabolic Biomarkers for Duchenne Muscular Dystrophy within a Natural History Study.

Boca Simina M SM Nishida Maki M Harris Michael M Rao Shruti S Cheema Amrita K AK Gill Kirandeep K Seol Haeri H Morgenroth Lauren P LP Henricson Erik E McDonald Craig C Mah Jean K JK Clemens Paula R PR Hoffman Eric P EP Hathout Yetrib Y Madhavan Subha S

PloS one 20160415 4

Serum metabolite profiling in Duchenne muscular dystrophy (DMD) may enable discovery of valuable molecular markers for disease progression and treatment response. Serum samples from 51 DMD patients from a natural history study and 22 age-matched healthy volunteers were profiled using liquid chromatography coupled to mass spectrometry (LC-MS) for discovery of novel circulating serum metabolites associated with DMD. Fourteen metabolites were found significantly altered (1% false discovery rate) in ...[more]

PMID: 27082433

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Project description:BackgroundDuchenne muscular dystrophy (DMD) is a disabling and life-threatening, X-linked recessive disorder caused by mutations in dystrophin. Natural history studies can inform the disease characteristics of DMD, and data from these studies can be used to plan and design clinical trials and as external controls for long-term studies. We report 12-month results from the largest natural history study of individuals with DMD in China receiving standard of care treatment.MethodsThis ongoing, multicentre, prospective, single-cohort study (ClinicalTrials.gov: NCT03760029) was conducted in Chinese male participants with DMD (ambulatory aged <6 years [Group 1; n = 99]; ambulatory aged ≥6 years [Group 2; n = 177], and non-ambulatory of any age [Group 3; n = 36]. The follow-up period is ≥24 months, with some participants followed for 30 months. The primary endpoint was time to clinical milestones due to DMD disease progression, and motor, pulmonary, and cardiac function. Secondary endpoints were quality of life (QoL) assessments.FindingsMean (standard deviation [SD]) age at screening was 3.4 (1.2), 8.6 (2.0), 12.3 (2.7) and 7.4 (3.5) years in Groups 1, 2, 3 and total respectively. Mean (SD) North Star Ambulatory Assessment (NSAA) total score at baseline was 21.2 (5.8) in Group 1, 19.5 (8.3) in Group 2 and 20.0 (7.7) in ambulatory total. Overall, the time to clinical milestones due to DMD disease progression was consistent with previous findings, in which loss of ambulation occurred at 13 years. There was a trend towards a decline over 12 months in NSAA and timed motor function from age 6 years, with the greatest reductions observed thereafter. There were no consistent trends in measures of QoL, although participants of any age generally had poorer outcomes at Month 12 versus their domain scores at baseline.InterpretationThis study improves the understanding of DMD progression according to the current standards of care in the Chinese DMD population and may inform selected endpoints and patient populations in clinical trials.FundingPfizer Inc.

Project description:Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca2+ influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our lab recently used two high-throughput multiplexing techniques (e.g., SomaScan® aptamer assay and tandem mass tag-(TMT) approach) and identified a series of serum protein biomarkers tied to different pathobiochemical pathways. In this study, we focused on validating the circulating levels of three proinflammatory chemokines (CCL2, CXCL10, and CCL18) that are believed to be involved in an early stage of muscle pathogenesis. We used highly specific and reproducible MSD ELISA assays and examined the association of these chemokines with DMD pathogenesis, age, disease severity, and response to glucocorticoid treatment. As expected, we confirmed that these three chemokines were significantly elevated in serum and muscle samples of DMD patients relative to age-matched healthy controls (p-value < 0.05, CCL18 was not significantly altered in muscle samples). These three chemokines were not significantly elevated in Becker muscular dystrophy (BMD) patients, a milder form of dystrophinopathy, when compared in a one-way ANOVA to a control group but remained significantly elevated in the age-matched DMD group (p < 0.05). CCL2 and CCL18 but not CXCL10 declined with age in DMD patients, whereas all three chemokines remained unchanged with age in BMD and controls. Only CCL2 showed significant association with time to climb four steps in the DMD group (r = 0.48, p = 0.038) and neared significant association with patients' reported outcome in the BMD group (r = 0.39, p = 0.058). Furthermore, CCL2 was found to be elevated in a serum of the mdx mouse model of DMD, relative to wild-type mouse model. This study suggests that CCL2 might be a suitable candidate biomarker for follow-up studies to demonstrate its physiological significance and clinical utility in DMD.

Dataset Information

Discovery of Metabolic Biomarkers for Duchenne Muscular Dystrophy within a Natural History Study.

Publications

Discovery of Metabolic Biomarkers for Duchenne Muscular Dystrophy within a Natural History Study.

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