Novel circulating serum proteins in Duchenne muscular dystrophy


Clinical Trials

Poster Number: M188


Fatemeh Ahmadiharchegani, Carleton University, Paula Clemens, MD, University of Pittsburgh, Michela Guglieri, Newcastle University and Newcastle Hospitals NHS Foundation Trust, VBP15-004 Investigators, CINRG, Eric Hoffman, PhD, Binghamton University, Binghamton, NY, USA, Utkarsh Dang, PhD, Carleton University, Yetrib Hathout, Phd, Binghamton University

Background: Noninvasive biomarkers are essential for understanding pathophysiological pathways, monitoring disease progression and response to therapies. Major advances in biomarker discovery in Duchenne muscular dystrophy (DMD) have occurred in the past few years, however, these have often involved low sample sizes, a recurrent issue in rare diseases, as well as possible confounding due to corticosteroid use and wide age ranges studied.
Objective: To compare serum protein levels between young, steroid-naïve, boys with DMD and unaffected healthy controls.
Methods: Pre-treatment samples (from 51 boys with DMD, 4 to < 7 years old) were obtained from a randomized clinical trial, VBP15-004. Along with 13 samples from controls, these were assayed using a Somalogic 7,000 aptamer panel with a data mask applied, limiting analysis to 1500 proteins based on literature and expert opinion. Biomarker levels were compared via empirical Bayes based moderated tests followed by multiple testing correction. A correlation-based cluster analysis was used to study biomarker-biomarker associations. Results: From the 1500 targets, 751 proteins were identified with mean altered levels between boys with DMD and unaffected controls. Multiple serum protein targets previously published in the literature were validated (muscle injury, inflammation, muscle regeneration, and extracellular remodeling). We expanded biomarkers associated with DMD cardiomyopathy, and alternative complement pathway regulation. Biomarkers showed grouping in established annotated groups increasing confidence in the biological relevance of the findings. Conclusions: This study used large group of steroid-naïve DMD patients in a narrow age range (4 to <7 years) studied to provide more precise estimation of fold change in biomarker levels between untreated DMD patients and healthy controls. Novel DMD biomarkers were identified, which will aid in understanding DMD pathogenesis at early stage of the disease, define potential therapeutic targets and also provide a broad palette of biomarkers to be employed in specific contexts of use.