Identification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles

• DOI: 10.1038/s41467-020-15971-w
• Publication Date: 2020-04-24T10:27:15Z
• Authors: Christine Péladeau; Nadine Adam; Lucas M. Bronicki; Adèle Coriati; Mohamed Thabet; Hasanen Al-Rewashdy; Jason Vanstone; Alan Mears; Jean-Marc Renaud; Martin Holcik; Bernard J. Jasmin
• Keywords: 0301 basic medicine; Utrophin; Science; Drug Evaluation, Preclinical; Internal Ribosome Entry Sites; Article; Cell Line; Myoblasts; Mice; 03 medical and health sciences; Peptide Elongation Factor 1; Animals; Humans; Pravastatin; Mice, Knockout; Q; Drug Repositioning; Betaxolol; Up-Regulation; 3. Good health; Muscular Dystrophy, Duchenne; Disease Models, Animal; Protein Biosynthesis; Mice, Inbred mdx; 5' Untranslated Regions

AbstractUp-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.