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.

Nature Communications
Department of Health Sciences

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