In vitro assessment of anti-fibrotic drug activity does not predict in vivo efficacy in murine models of Duchenne muscular dystrophy

Fibrosis is the most common complication from chronic diseases, and yet no therapy capable of mitigating its effects available. Our goal to unveil specific signaling regulating fibrogenic process identify potential small molecule candidates that block differentiation fibro/adipogenic progenitors. We performed a large-scale drug screen using muscle-resident progenitors mouse model expressing EGFP under Collagen1a1 promotor. first confirmed was expressed in response TGF?1 stimulation vitro. Then we treated cells with alone or drugs two libraries known compounds. The ability quantified by imaging flow cytometry. From two-rounds screening, positive hits were tested vivo mice for Duchenne Muscular Dystrophy (mdx mice). histopathology muscles assessed picrosirius red (fibrosis) laminin staining (myofiber size). vitro identified 21 3 on mdx mice. None three significantly improved muscle histopathology. various efficient compounds, none them strongly inhibited fibrosis skeletal To explain these observations, hypothesize Dystrophy, which secondary event due degeneration inflammation, could have adverse effect regeneration balancing off any leading absence significant results.