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• W4387310323 abstract "Chronic inflammation is a major driver of Duchenne Muscular Dystrophy (DMD) disease and inflammation persists even after patients are treated with FDA-approved dystrophin restoration therapies. Thus, there is an urgent need for pre-clinical dystrophy models that dissect the molecular underpinnings of chronic inflammation to inform current and future treatment regimens. miRNAs play a key role in regulating inflammatory signaling. 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 (UTR) and reduce dystrophin protein in DMD exon skipping therapies, Becker Muscular Dystrophy (BMD), and inflammatory myositis. We identified NF-kB consensus elements in the promoter/enhancer regions of inflamma-miRs, and demonstrated inflammation drives inflamma-miR expression, reducing dystrophin, further activating inflammatory signaling, and causing a self-sustaining pathological feedback loop. Supporting inflamma-miR regulation via NF-kB, we show treatment with the anti-inflammatory drug vamorolone reduces inflamma-miRs in DMD model (mdx) mice and our preliminary data shows in low-dystrophin expressing bmd mice created by our lab, vamorolone reduces inflamm-miRs and increases dystrophin protein levels by 50%. These data also suggest inflamma-miR reduction can increase expression of truncated dystrophin isoforms (e.g., exon skipping/BMD). Interestingly, two inflamma-miRs (miR-146a, miR-142-3p) resemble viral RNA, the natural ligand for Toll-like receptor 7 (TLR7). Several reports show “viral like” miRNAs act as novel TLR7 ligands. In vitro, we show miR-146a and miR-142-3p bind to TLR7 and activate pro-inflammatory cytokine secretion, while either mutation of uridine-rich regions of miRNAs or CRISPR-mediated deletion of TLR7 prevents activation. While in a healthy state TLR7 expression is confined to immune cells, we find TLR7 is inappropriately expressed in diseased muscle suggesting inflamed muscle is primed to sense viral-like miRNAs. Collectively, our data provide evidence for targeting dystrophin-targeting inflamma-miRs as a therapeutic mechanism to increase dystrophin in combination with exon skipping in DMD or as a stand-alone therapy in BMD. Further, they suggest that inflamma-miR-TLR7 interactions could serve as a novel therapeutic target to “turn off” the pathological inflammatory feedback loop in dystrophic muscle. Chronic inflammation is a major driver of Duchenne Muscular Dystrophy (DMD) disease and inflammation persists even after patients are treated with FDA-approved dystrophin restoration therapies. Thus, there is an urgent need for pre-clinical dystrophy models that dissect the molecular underpinnings of chronic inflammation to inform current and future treatment regimens. miRNAs play a key role in regulating inflammatory signaling. 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 (UTR) and reduce dystrophin protein in DMD exon skipping therapies, Becker Muscular Dystrophy (BMD), and inflammatory myositis. We identified NF-kB consensus elements in the promoter/enhancer regions of inflamma-miRs, and demonstrated inflammation drives inflamma-miR expression, reducing dystrophin, further activating inflammatory signaling, and causing a self-sustaining pathological feedback loop. Supporting inflamma-miR regulation via NF-kB, we show treatment with the anti-inflammatory drug vamorolone reduces inflamma-miRs in DMD model (mdx) mice and our preliminary data shows in low-dystrophin expressing bmd mice created by our lab, vamorolone reduces inflamm-miRs and increases dystrophin protein levels by 50%. These data also suggest inflamma-miR reduction can increase expression of truncated dystrophin isoforms (e.g., exon skipping/BMD). Interestingly, two inflamma-miRs (miR-146a, miR-142-3p) resemble viral RNA, the natural ligand for Toll-like receptor 7 (TLR7). Several reports show “viral like” miRNAs act as novel TLR7 ligands. In vitro, we show miR-146a and miR-142-3p bind to TLR7 and activate pro-inflammatory cytokine secretion, while either mutation of uridine-rich regions of miRNAs or CRISPR-mediated deletion of TLR7 prevents activation. While in a healthy state TLR7 expression is confined to immune cells, we find TLR7 is inappropriately expressed in diseased muscle suggesting inflamed muscle is primed to sense viral-like miRNAs. Collectively, our data provide evidence for targeting dystrophin-targeting inflamma-miRs as a therapeutic mechanism to increase dystrophin in combination with exon skipping in DMD or as a stand-alone therapy in BMD. Further, they suggest that inflamma-miR-TLR7 interactions could serve as a novel therapeutic target to “turn off” the pathological inflammatory feedback loop in dystrophic muscle." @default.
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• W4387310323 date "2023-10-01" @default.
• W4387310323 modified "2023-10-07" @default.
• W4387310323 title "P261 The role of pathological miRNAs in Duchenne and Becker muscular dystrophy" @default.
• W4387310323 doi "https://doi.org/10.1016/j.nmd.2023.07.324" @default.
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