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

LIFE SCIENCES

卷:279

Article

Theret, Marine^1,2  Low, Marcela^1,2  Rempel, Lucas^1,2  Li, Fang Fang^1,2  Tung, Lin Wei^1,2  Contreras, Osvaldo^3,4,5  Chang, Chih-Kai^1,2  Wu, Andrew^1,2  Soliman, Hesham^1,2,6  Rossi, Fabio M. V.^1,2 

[1] Dept Med Genet, Sch Biomed Engn, 2222 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada

[2] Dept Med Genet, Biomed Res Ctr, 2222 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada

[3] Victor Chang Cardiac Res Inst, Dev & Stem Cell Biol Div, Darlinghurst, NSW 2010, Australia

[4] Pontificia Univ Catolica Chile, Fac Ciencias Biol, Dept Biol Celular & Mol, Santiago 8331150, Chile

[5] Pontificia Univ Catolica Chile, Ctr Aging & Regenerat CARE ChileUC, Santiago 8331150, Chile

[6] Minia Univ, Fac Pharmaceut Sci, Dept Pharmacol & Toxicol, Al Minya, Egypt

关键词: Drug screening;    Fibro;    adipogenic progenitors;    Fibrosis;    Repair;    Skeletal muscle;   

DOI  :  10.1016/j.lfs.2021.119482

来源: Elsevier

【 摘 要 】

Aim: 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. Method: 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). Key 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. Significance: 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.

【 授权许可】

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