Identification of disease-specific biomarker signatures in the serum of young children with COL6 and LAMA2-related dystrophies

Topic:

Translational Research

Poster Number: 260 T

Author(s):

A. Reghan Foley, MD, MD(Res), Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, Justin K. Moy, MS, Bioinformatics Program, Boston University, Anna V. Golubeva, PhD, Department of Anatomy and Neuroscience, University College Cork, Ying Hu, MS, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, Darina Sheehan, MSc, INFANT Research Centre, University College Cork, Kory R. Johnson, PhD, Bioinformatics Section, NINDS, National Institutes of Health, Monkol Lek, PhD, Yale University, Jane A. English, PhD, Department of Anatomy and Neuroscience and INFANT Research Centre, University College Cork, Deirdre M. Murray, PhD, INFANT Research Centre and Department of Paediatrics and Child Health, Carsten G. Bönnemann, MD, habil., Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health

With promising therapies in development for the congenital muscular dystrophy subtypes COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs), and an absence of blood biomarkers, we pursued discovery biomarker research in search of disease and disease stage-specific profiles in COL6-RDs and LAMA2-RDs for improving clinical trial readiness. To identify novel biomarkers, we created a large age-matched multi-omic collection of miRNA and proteomics data in young patients with COL6-RD or LAMA2-RD, and healthy controls. Patient serum samples were collected at the NIH Clinical Center (USA). Control samples were collected at the University College Cork INFANT Research Centre (Ireland). Serum from patients with COL6-RD (N=18) and LAMA2-RD (N=14) ages 5-79 months and age and sex-matched controls (N=34) were analyzed along with detailed phenotypic data. Our bioinformatics analysis identified 2632 miRNAs and 388 proteins which we analyzed for differential expression in COL6-RDs and LAMA2-RDs. We preliminarily identified significant age-related miRNAs and proteins in COL6-RDs versus controls and LAMA2-RDs versus controls, which may represent disease stage-specific biomarkers. Furthermore, using Ingenuity Pathway Analysis (Qiagen), we identified significantly dysregulated gene networks and hub genes that may contribute to COL6-RD and LAMA2-RD pathology. Given that COL6-RDs and LAMA2-RDs share congenital-onset dystrophic pathomechanisms – and pathology related miRNA and proteomic markers circulate in blood – our research provides a robust dataset and key directions to develop minimally invasive miRNA and serum proteome marker profiles to monitor disease stage and potential therapeutic responsiveness in these CMDs with high unmet therapeutic need.