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

Pietro Spitali, Kristina Hettne, Roula Tsonaka, Mohammed Charrout, Janneke van den Bergen, Zaïda Koeks, Hermien E. Kan, Melissa T. Hooijmans, Andreas Roos, Volker Straub, Francesco Muntoni, Cristina Al-Khalili-Szigyarto, Marleen J. A. Koel-Simmelink, Charlotte E. Teunissen, Hanns Lochmüller, Erik H. Niks, Annemieke Aartsma-Rus

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)715-726
JournalJournal of Cachexia, Sarcopenia and Muscle
Volume9
Issue number4
DOIs
Publication statusPublished - 2018

Cite this

Spitali, P., Hettne, K., Tsonaka, R., Charrout, M., van den Bergen, J., Koeks, Z., ... Aartsma-Rus, A. (2018). Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies. Journal of Cachexia, Sarcopenia and Muscle, 9(4), 715-726. https://doi.org/10.1002/jcsm.12304
Spitali, Pietro ; Hettne, Kristina ; Tsonaka, Roula ; Charrout, Mohammed ; van den Bergen, Janneke ; Koeks, Zaïda ; Kan, Hermien E. ; Hooijmans, Melissa T. ; Roos, Andreas ; Straub, Volker ; Muntoni, Francesco ; Al-Khalili-Szigyarto, Cristina ; Koel-Simmelink, Marleen J. A. ; Teunissen, Charlotte E. ; Lochmüller, Hanns ; Niks, Erik H. ; Aartsma-Rus, Annemieke. / Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies. In: Journal of Cachexia, Sarcopenia and Muscle. 2018 ; Vol. 9, No. 4. pp. 715-726.
@article{5ad4d3c2dd2a45f58a2fa4e0bf0c44e9,
title = "Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies",
abstract = "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.",
author = "Pietro Spitali and Kristina Hettne and Roula Tsonaka and Mohammed Charrout and {van den Bergen}, Janneke and Za{\"i}da Koeks and Kan, {Hermien E.} and Hooijmans, {Melissa T.} and Andreas Roos and Volker Straub and Francesco Muntoni and Cristina Al-Khalili-Szigyarto and Koel-Simmelink, {Marleen J. A.} and Teunissen, {Charlotte E.} and Hanns Lochm{\"u}ller and Niks, {Erik H.} and Annemieke Aartsma-Rus",
year = "2018",
doi = "10.1002/jcsm.12304",
language = "English",
volume = "9",
pages = "715--726",
journal = "Journal of Cachexia, Sarcopenia and Muscle",
issn = "2190-5991",
publisher = "Wiley-Blackwell",
number = "4",

}

Spitali, P, Hettne, K, Tsonaka, R, Charrout, M, van den Bergen, J, Koeks, Z, Kan, HE, Hooijmans, MT, Roos, A, Straub, V, Muntoni, F, Al-Khalili-Szigyarto, C, Koel-Simmelink, MJA, Teunissen, CE, Lochmüller, H, Niks, EH & Aartsma-Rus, A 2018, 'Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies' Journal of Cachexia, Sarcopenia and Muscle, vol. 9, no. 4, pp. 715-726. https://doi.org/10.1002/jcsm.12304

Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies. / Spitali, Pietro; Hettne, Kristina; Tsonaka, Roula; Charrout, Mohammed; van den Bergen, Janneke; Koeks, Zaïda; Kan, Hermien E.; Hooijmans, Melissa T.; Roos, Andreas; Straub, Volker; Muntoni, Francesco; Al-Khalili-Szigyarto, Cristina; Koel-Simmelink, Marleen J. A.; Teunissen, Charlotte E.; Lochmüller, Hanns; Niks, Erik H.; Aartsma-Rus, Annemieke.

In: Journal of Cachexia, Sarcopenia and Muscle, Vol. 9, No. 4, 2018, p. 715-726.

Research output: Contribution to journalArticleAcademicpeer-review

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

PY - 2018

Y1 - 2018

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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85052068809&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/29682908

U2 - 10.1002/jcsm.12304

DO - 10.1002/jcsm.12304

M3 - Article

VL - 9

SP - 715

EP - 726

JO - Journal of Cachexia, Sarcopenia and Muscle

JF - Journal of Cachexia, Sarcopenia and Muscle

SN - 2190-5991

IS - 4

ER -