A novel drug-combination screen in zebrafish identifies epigenetic small molecule candidates for Duchenne muscular dystrophy

Abstract

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.

Modeling neuromuscular diseases in zebrafish

“…tested epigenetic small molecules from the Cayman Chemical Epigenetics Screening Library on dmd mutant zebrafish line sapje. They developed a grid system containing 403 chemical pools, which would allow testing of each compound in the library in combination with every other library compound at least once (Farr et al, 2020). Their method was validated against TSA-containing chemical pools which rescued the skeletal muscle phenotype in sapje zebrafish.…”

“…In contrast, individual testing of each compound from the pool did not show any significant effect, highlighting the use of combinations of drugs for future therapeutic approaches. Oxaflatin in combination with salermide significantly improved the dmd mutant muscle birefringence, without rescuing dystrophin levels (Farr et al, 2020). Further studies would be needed to determine if oxaflatin and salermide work in an additive or synergistic manner.…”