Epigenetic small molecule screening identifies a new HDACi compound for ameliorating Duchenne muscular dystrophy.

Abstract

Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease. There are currently few effective therapies to treat the disease, although many approaches are being pursued. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish models, and the HDACi givinostat has recently gained FDA approval for DMD. Our goal was to identify additional HDACi, or other classes of epigenetic small molecules, that are beneficial for DMD. Using an established animal model for DMD, the zebrafish dmd mutant strain sapje, we screened a library of over 800 epigenetic small molecules. Our screening identified a new HDACi, SR-4370, that ameliorated dmd mutant zebrafish skeletal muscle degeneration, as well as additional HDACi that have previously been shown to improve dmd zebrafish. We find that a single early treatment of HDACi can ameliorate the muscle phenotype and increase lifespan in dmd zebrafish. Furthermore, we find that HDACi treatments that improve dmd muscle also cause increased histone acetylation in zebrafish larvae. Our results add to the growing evidence that HDACi are promising candidates for treating DMD. Our study also provides further support for the effectiveness of small molecule screening in dmd zebrafish.