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

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dc.contributor.authorContreras, Osvaldo
dc.date.accessioned2023-05-19T20:49:55Z
dc.date.available2023-05-19T20:49:55Z
dc.date.issued2021
dc.description.abstractAim: Fibrosis is the most common complication from chronic diseases, and yet no therapy capable of mitigating its effects is available. Our goal is to unveil specific signaling regulating the fibrogenic process and to identify potential small molecule candidates that block fibrogenic differentiation of fibro/adipogenic progenitors.
dc.description.abstractMethod: We performed a large-scale drug screen using muscle-resident fibro/adipogenic progenitors from a mouse model expressing EGFP under the Collagen1a1 promotor. We first confirmed that the EGFP was expressed in response to TGF beta 1 stimulation in vitro. Then we treated cells with TGF beta 1 alone or with drugs from two libraries of known compounds. The drugs ability to block the fibrogenic differentiation was quantified by imaging and flow cytometry. From a two-rounds screening, positive hits were tested in vivo in the mice model for the Duchenne Muscular Dystrophy (mdx mice). The histopathology of the muscles was assessed with picrosirius red (fibrosis) and laminin staining (myofiber size).
dc.description.abstractKey findings: From the in vitro drug screening, we identified 21 drugs and tested 3 in vivo on the mdx mice. None of the three drugs significantly improved muscle histopathology.
dc.description.abstractSignificance: The in vitro drug screen identified various efficient compounds, none of them strongly inhibited fibrosis in skeletal muscle of mdx mice. To explain these observations, we hypothesize that in Duchenne Muscular Dystrophy, in which fibrosis is a secondary event due to chronic degeneration and inflammation, the drugs tested could have adverse effect on regeneration or inflammation, balancing off any positive effects and leading to the absence of significant results.
dc.fechaingreso.objetodigital2024-12-20
dc.fuente.origenORCID-mayo23
dc.identifier.doi10.1016/j.lfs.2021.119482
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/70095
dc.identifier.wosidWOS:000664117000005
dc.language.isoen
dc.nota.accesocontenido parcial
dc.revistaLife Sciences
dc.rightsacceso restringido
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleIn vitro assessment of anti-fibrotic drug activity does not predict in vivo efficacy in murine models of Duchenne muscular dystrophyes_ES
dc.typeartículo
dc.volumenVol. 279
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