Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5’UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway.

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Persistent URL dx.doi.org/10.1038/s41467-020-15971-w
Journal Nature Communications
Péladeau, C. (Christine), Adam, N. (Nadine), Bronicki, L.M. (Lucas M.), Coriati, A. (Adèle), Thabet, M. (Mohamed), Al-Rewashdy, H. (Hasanen), … Jasmin, B.J. (Bernard J.). (2020). Identification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles. Nature Communications, 11(1). doi:10.1038/s41467-020-15971-w