SR-4370

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 animal 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 zebrafishdmdmutant strainsapje, we screened a library of over 800 epigenetic small molecules of various classes. We used a quantitative muscle birefringence assay to assess and compare the effects of these small molecule treatments ondmdmutant zebrafish skeletal muscle. Our screening identified a new HDACi, SR-4370, that ameliorateddmdmutant zebrafish skeletal muscle degeneration, in addition to HDACi previously shown to improvedmdzebrafish. We find that a single early treatment of HDACi can amelioratedmdzebrafish. Furthermore, we find that HDACi that improvedmdmuscle also cause increased histone acetylation in zebrafish larvae, whereas givinostat does not appear to increase histone acetylation or improve zebrafishdmdmuscle. 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 indmdzebrafish.