RT Journal Article
SR Electronic
T1 A novel drug-combination screen in zebrafish identifies epigenetic small molecule candidates for Duchenne muscular dystrophy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.19.956532
DO 10.1101/2020.02.19.956532
A1 Gist H. Farr III
A1 Melanie Morris
A1 Arianna Gomez
A1 Thao Pham
A1 Elizabeth U. Parker
A1 Elisabeth Kilroy
A1 Shery Said
A1 Clarissa Henry
A1 Lisa Maves
YR 2020
UL http://biorxiv.org/content/early/2020/02/20/2020.02.19.956532.abstract
AB Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder and is one of the most common muscular dystrophies. There are currently few effective therapies to treat the disease, although many small-molecule approaches are being pursued. Specific histone deacetylase inhibitors (HDACi) can ameliorate DMD phenotypes in mouse and zebrafish animal models and have also shown promise for DMD in clinical trials. However, beyond these HDACi, other classes of epigenetic small molecules have not been broadly and systematically studied for their benefits for DMD. Here, we performed a novel chemical screen of a library of epigenetic compounds using the zebrafish dmd model. We identified candidate pools of epigenetic compounds that improve skeletal muscle structure in dmd zebrafish. We then identified a specific combination of two drugs, oxamflatin and salermide, that significantly rescued dmd zebrafish skeletal muscle degeneration. Furthermore, we validated the effects of oxamflatin and salermide in an independent laboratory. Our results provide novel, effective methods for performing a combination small-molecule screen in zebrafish. Our results also add to the growing evidence that epigenetic small molecules may be promising candidates for treating DMD.