Preclinical characterization of antagomiR-218 as a potential treatment for Myotonic Dystrophy

Myotonic Dystrophy (DM1) is a rare neuromuscular disease caused by the expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts fold into hairpins that sequester MBNL1 proteins in ribonuclear foci, depletion of MBNL1 being a chief contribution to disease symptoms such as muscle weakness and atrophy, and myotonia. Thus, the upregulation of endogenous MBNL1 levels may compensate for the sequestration. We have demonstrated that antisense oligonucleotides against miR-218 boost expression of MBNL1 and rescue phenotypes in disease models. Here we provide a preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myoblasts. In HSALR, antagomiR-218 rescued molecular and functional phenotypes in a dose-dependent manner, showed a good toxicity profile, and lasted some 15 days after a single subcutaneous injection. In muscle tissue, the antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the percentage of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient myoblasts. Importantly, miR-218 was found upregulated in DM1 muscle biopsies, which makes this miRNA a relevant therapeutic target. Overall design: We compare 3 replicas of healthy myoblasts, DM1 myoblasts and DM1 myoblasts treated with antagomiR-218