Abstract
There is a growing need for accurate, reliable and minimally-invasive biomarkers for monitoring DMD progression and response to treatment. microRNAs (miRNAs) are an attractive disease biomarker candidate due to their straightforward isolation from biofluids and known dysregulation in DMD patients. Previous cross-sectional studies identified dysregulation of several muscle-specific miRNAs in DMD patients. However, to date, no longitudinal studies have been performed. We performed the first miRNA profiling studies on free-circulating (fc) and exosomal (ex) miRNAs isolated from DMD patients' plasma, aiming to find novel cross-sectionally and longitudinally dysregulated miRNAs. Plasma was collected from 14 controls, 29 ambulant (A) and 17 non-ambulant (NA) DMD patients. Longitudinal fc-miRNA expression patterns were evaluated between two time-points in ambulant (n=7) and non-ambulant (n=2) DMD patients. MiRNA profiling and validation studies revealed longitudinal upregulation of fc-miR-1-3p and miR-122-5p in A DMD patients compared to controls. Cross-sectional analysis revealed one novel fc-miRNA and two novel ex-miRNAs significantly upregulated in DMD compared to controls, and a novel miRNA dysregulated between A and NA DMD patients. Dysregulated miRNAs significantly correlated with clinical functional tests, including ex-miR-29 with several lower limb measures and ex-miR-33a-5p with grip strength. Additionally, miR-29c-3p expression (fc & ex) was significantly downregulated in patients taking intermittent corticosteroids compared to controls. We confirmed the dysregulation of previously-published miRNAs and five novel free-circulating and exosomal miRNAs in DMD patients. MiR-29c-3p, a fibrosis-regulator, was down-regulated in DMD patients, exosomal expression correlated with functional measures and its levels were also modulated by daily corticosteroid therapy. Therefore, miR-29-3p is a promising biomarker in DMD.
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