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<p>Blood-accessible biomarkers offer promising insights into the pathogenesis of Duchenne muscular dystrophy (DMD) and other muscle diseases. Here, we quantified the relative abundance of 7,289 serum proteins using SomaScan proteomics in pre-treatment samples from 51 boys with DMD (aged 4 to &lt;7) and 13 healthy controls from the VISION DMD (VBP15-004) trial. An independent validation cohort of untreated DMD boys (aged 4 to &lt;8) from the FOR-DMD trial was also analyzed. Of the proteins screened, 26% and 15% were significantly elevated and decreased, respectively, in the serum of young DMD boys compared to controls (adjusted p-value &lt; 0.05). A high correlation (Spearman r = 0.85) in fold changes was observed between the two datasets. Many proteins with altered levels overlapped with known markers of muscle injury, inflammation, regeneration, and extracellular matrix remodeling. Selected biomarkers were queried in two published muscle mRNA and a muscle snRNAseq dataset in DMD biopsies. Novel factors involved in muscle regeneration and ECM remodeling were identified. This larger-scale, multi-clinical trial-based cohort study in untreated DMD boys substantially expands the catalog of circulating biomarkers, highlighting early-stage pathological processes. These findings can help identify new therapeutic targets and develop clinically actionable biomarkers to assess disease progression and response to therapies.</p>

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Circulating protein biomarkers identified in two independent clinical trial cohorts of glucocorticoid-naive Duchenne muscular dystrophy patients.

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Fatemeh Ahmadiharchegani,
  • Rebecca A. Tobin,
  • Chiara Degan,
  • Ahmed Naveed,
  • Michela Guglieri,
  • Albert Jiménez-Requena,
  • Sharon I. de Vries,
  • Cristina Al-Khalili Szigyarto,
  • Pietro Spitali,
  • Roula Tsonaka,
  • Yuri E. M. van der Burgt,
  • Jordi Diaz-Manera,
  • Jesse M. Damsker,
  • Seth J. Perlman,
  • Edward C. Smith,
  • Iain Horrocks,
  • Richard S. Finkel,
  • Jean K. Mah,
  • Nicolas Deconinck,
  • Nathalie M. Goemans,
  • Jana Haberlová,
  • Volker Straub,
  • Laurel Mengle-Gaw,
  • Benjamin D. Schwartz,
  • Amy Harper,
  • Perry B. Shieh,
  • Liesbeth De Waele,
  • Diana Castro,
  • Michele L. Yang,
  • Monique M. Ryan,
  • Craig M. McDonald,
  • Erik K. Henricson,
  • Erica Goude,
  • Mar Tulinius,
  • Richard I. Webster,
  • Hugh J. Mcmillan,
  • Nancy Kuntz,
  • Vamshi K. Rao,
  • Giovanni Baranello,
  • Stefan Spinty,
  • Anne-Marie Childs,
  • Annie M. Sbrocchi,
  • Kathryn A. Selby,
  • Migvis Monduy,
  • Yoram Nevo,
  • Juan J. Vilchez,
  • Andres Nascimento-Osorio,
  • Erik H. Niks,
  • Imelda JM De Groot,
  • Marina Katsalouli,
  • John N. Van DenAnker,
  • Leanne M. Ward,
  • Mika Leinonen,
  • Tina Duong,
  • Carolina Tesi Rocha,
  • Mathula Thangarajh,
  • MD Andrea L. D’Alessandro,
  • Lauren P. Morgenroth,
  • Kate Bushby,
  • Michael P. McDermott,
  • Kimberly A. Hart,
  • Rabi Tawil,
  • William B. Martens,
  • Barbara E. Herr,
  • Elaine McColl,
  • Chris Speed,
  • Jennifer Wilkinson,
  • Janbernd Kirschner,
  • Wendy M. King,
  • Michelle Eagle,
  • Mary W. Brown,
  • Tracey Willis,
  • Robert C. Griggs,
  • Volker Straub,
  • Henriette van Ruiten,
  • Anne-Marie Childs,
  • Emma Ciafaloni,
  • Perry B. Shieh,
  • Stefan Spinty,
  • Lorenzo Maggi,
  • Giovanni Baranello,
  • Russell J. Butterfield,
  • IA Horrocks,
  • Helen Roper,
  • Zoya Alhaswani,
  • Kevin M. Flanigan,
  • Nancy L. Kuntz,
  • Adnan Manzur,
  • Basil T. Darras,
  • Peter B. Kang,
  • Leslie Morrison,
  • Monika Krzesniak-Swinarska,
  • Jean K. Mah,
  • Tiziana E. Mongini,
  • Federica Ricci,
  • Maja von der Hagen,
  • Richard S. Finkel,
  • Kathleen O’Reardon,
  • Matthew Wicklund,
  • Ashutosh Kumar,
  • Craig M. McDonald,
  • Jay J. Han,
  • Nanette Joyce,
  • Erik K. Henricson,
  • Ulrike Schara-Schmidt,
  • Andrea Gangfus,
  • Ekkehard Wilichowski,
  • Richard J. Barohn,
  • Jeffrey M. Statland,
  • Craig Campbell,
  • Giuseppe Vita,
  • Gian Luca Vita,
  • James FHoward,
  • Imelda Hughes,
  • Hugh J. McMillan,
  • Elena Pegoraro,
  • Luca Bello,
  • WBryan Burnette,
  • Mathula Thangarajh,
  • Taeun Chang,
  • Paula R. Clemens,
  • Eric P. Hoffman,
  • Utkarsh J. Dang,
  • Yetrib Hathout

摘要

Blood-accessible biomarkers offer promising insights into the pathogenesis of Duchenne muscular dystrophy (DMD) and other muscle diseases. Here, we quantified the relative abundance of 7,289 serum proteins using SomaScan proteomics in pre-treatment samples from 51 boys with DMD (aged 4 to <7) and 13 healthy controls from the VISION DMD (VBP15-004) trial. An independent validation cohort of untreated DMD boys (aged 4 to <8) from the FOR-DMD trial was also analyzed. Of the proteins screened, 26% and 15% were significantly elevated and decreased, respectively, in the serum of young DMD boys compared to controls (adjusted p-value < 0.05). A high correlation (Spearman r = 0.85) in fold changes was observed between the two datasets. Many proteins with altered levels overlapped with known markers of muscle injury, inflammation, regeneration, and extracellular matrix remodeling. Selected biomarkers were queried in two published muscle mRNA and a muscle snRNAseq dataset in DMD biopsies. Novel factors involved in muscle regeneration and ECM remodeling were identified. This larger-scale, multi-clinical trial-based cohort study in untreated DMD boys substantially expands the catalog of circulating biomarkers, highlighting early-stage pathological processes. These findings can help identify new therapeutic targets and develop clinically actionable biomarkers to assess disease progression and response to therapies.