TY - JOUR
T1 - Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies
AU - Spitali, Pietro
AU - Hettne, Kristina
AU - Tsonaka, Roula
AU - Charrout, Mohammed
AU - van den Bergen, Janneke
AU - Koeks, Zaïda
AU - Kan, Hermien E.
AU - Hooijmans, Melissa T.
AU - Roos, Andreas
AU - Straub, Volker
AU - Muntoni, Francesco
AU - Al-Khalili-Szigyarto, Cristina
AU - Koel-Simmelink, Marleen J.A.
AU - Teunissen, Charlotte E.
AU - Lochmüller, Hanns
AU - Niks, Erik H.
AU - Aartsma-Rus, Annemieke
N1 - © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Background: Analysis 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. Methods: A 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. Results: Cross-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. Conclusions: Serum 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.
AB - Background: Analysis 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. Methods: A 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. Results: Cross-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. Conclusions: Serum 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.
KW - Adult
KW - Aged
KW - Biomarkers
KW - Computational Biology/methods
KW - Cross-Sectional Studies
KW - Disease Progression
KW - Follow-Up Studies
KW - Humans
KW - Middle Aged
KW - Muscle, Skeletal/diagnostic imaging
KW - Muscular Dystrophy, Duchenne/diagnosis
KW - Proteome
KW - Proteomics/methods
KW - Young Adult
UR - http://www.scopus.com/inward/record.url?scp=85052068809&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85052068809&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29682908
U2 - https://doi.org/10.1002/jcsm.12304
DO - https://doi.org/10.1002/jcsm.12304
M3 - Article
C2 - 29682908
SN - 2190-5991
VL - 9
SP - 715
EP - 726
JO - Journal of cachexia, sarcopenia and muscle
JF - Journal of cachexia, sarcopenia and muscle
IS - 4
ER -