The role of inflamma-miRs in Duchenne and Becker Muscular Dystrophy


Pre-Clinical Research

Poster Number: S12


Alyson Fiorillo, PhD, Virginia Commonwealth University

Chronic inflammation persists in DMD even after patients are treated with FDA-approved dystrophin restoration therapies. miRNAs play a key role in regulating inflammation. Our laboratory has characterized two miRNA panels that are elevated in dystrophic muscle, collectively referred to as inflamma-miRs. A subset of inflamma-miRs bind to the dystrophin 3′ untranslated region and reduce dystrophin protein in DMD exon skipping and in BMD. The pro-inflammatory transcription factor NF-kB regulates inflamma-miR expression, reducing dystrophin, further activating inflammatory signaling, and causing a self-sustaining pathological feedback loop. We show treatment with the anti-inflammatory drug vamorolone reduces inflamma-miRs in DMD model (mdx) mice. Vamorolone also reduces inflamm-miRs and increases dystrophin protein levels by 50% in novel BMD model (bmx) mice. Additionally, genetic deletion of a single inflamma-miR (miR-146a) increases dystrophin restoration in exon skipping treated mdx mice. Interestingly, two inflamma-miRs (miR-146a, miR-142-3p) resemble viral RNA, the ligand for TLR7. Several reports show “viral like” miRNAs act as novel TLR7 ligands. We find miR-146a and miR-142-3p bind TLR7 and activate TNF-α secretion, while either mutation of uridine-rich regions of miRNAs or deletion of TLR7 prevents activation. While in healthy tissue TLR7 expression is confined to immune cells, TLR7 is mis-expressed in DMD and BMD suggesting these muscles are primed to sense viral-like miRNAs. Collectively, our data provide evidence that inflamma-miR inhibition could benefit dystrophin restoration when combined with exon skipping in DMD, or as a stand-alone therapy in BMD. Further, they suggest inflamma-miR-TLR7 interactions could potentially be targeted to attenuate pathological inflammation in dystrophic muscle.