P.235 - Circulating miRs biomarkers for therapeutic monitoring in utrophin based DMD therapy

Abstract

Duchenne muscular dystrophy (DMD) is a severe neuromuscular pathology that results in progressive muscle weakness, paralysis and premature death. The disorder is caused by mutations which result in the absence of dystrophin, a protein localized underneath the sarcolemma. In collaboration with summit therapeutics plc, the Davies Lab has developed a promising therapeutic approach applicable to all DMD patients based on the modulation of utrophin, a structural and functional paralogue of dystrophin, to compensate its absence and ameliorate the dystrophic phenotype. One small molecule, ezumtromid is currently in clinical trial. Muscle biopsies are highly invasive so there is an urgent need to develop new approaches to measure efficacy of utrophin modulation clinical trials. Our project intends to decipher the miRome of serum from different murine models including wild-type, the dystrophic mdx, the transgenic mdx-Fiona mice expressing high levels of utrophin and the double knockout utrophin/dystrophin (dko) in order to provide a comprehensive description of myomiRs in these different utrophin contexts. Diverse miRNAs including miR-1, miR-133 and miR-206 have been previously described as highly elevated biomarkers in serum of mdx mice as well in DMD patients. Interestingly, their levels decreased in exon skipping therapy and were correlated to dystrophin restoration. These observations demonstrate the important role of circulating miRNAs as reliable biomarkers to monitor disease progression and response to treatment in DMD. A molecular profile of these miRNAs in mdx model and its modification by utrophin expression will allow us to compare utrophin modulation with other DMD therapies. Overall, our results should facilitate the clinical translation of utrophin modulation DMD therapy.