A novel chemical-combination screen in zebrafish identifies epigenetic small molecule candidates for the treatment of Duchenne muscular dystrophy

Autor: Shery Said, Lisa Maves, Elizabeth U. Parker, Gist H. Farr, Thao Pham, Clarissa A. Henry, Arianna Gomez, Melanie Morris, Elisabeth A. Kilroy
Rok vydání: 2020
Předmět:
musculoskeletal diseases
Duchenne muscular dystrophy
0301 basic medicine
congenital
hereditary
and neonatal diseases and abnormalities
lcsh:Diseases of the musculoskeletal system
Muscle Proteins
Naphthols
Hydroxamic Acids
Epigenesis
Genetic
Small Molecule Libraries
Histone H4
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
HDAC inhibitors
Drug Discovery
medicine
Animals
Orthopedics and Sports Medicine
Epigenetics
Muscle
Skeletal
Givinostat
Molecular Biology
Zebrafish
Cells
Cultured
Epigenetic small molecules
Phenylpropionates
biology
Research
Membrane Proteins
Skeletal muscle
Cell Biology
Chemical screen
Zebrafish Proteins
biology.organism_classification
medicine.disease
High-Throughput Screening Assays
Cell biology
Histone Deacetylase Inhibitors
Muscular Dystrophy
Duchenne
Oxamflatin
030104 developmental biology
medicine.anatomical_structure
chemistry
Histone deacetylase
lcsh:RC925-935
030217 neurology & neurosurgery
Zdroj: Skeletal Muscle
Skeletal Muscle, Vol 10, Iss 1, Pp 1-17 (2020)
ISSN: 2044-5040
Popis: Background 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. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish animal models. The HDACi givinostat has shown promise for DMD in clinical trials. However, beyond a small group of HDACi, other classes of epigenetic small molecules have not been broadly and systematically studied for their benefits for DMD. Methods We used an established animal model for DMD, the zebrafish dmd mutant strain sapje. A commercially available library of epigenetic small molecules was used to treat embryonic-larval stages of dmd mutant zebrafish. We used a quantitative muscle birefringence assay in order to assess and compare the effects of small-molecule treatments on dmd mutant zebrafish skeletal muscle structure. Results We performed a novel chemical-combination 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 mutant zebrafish. We then identified a specific combination of two HDACi compounds, oxamflatin and salermide, that ameliorated dmd mutant zebrafish skeletal muscle degeneration. We validated the effects of oxamflatin and salermide on dmd mutant zebrafish in an independent laboratory. Furthermore, we showed that the combination of oxamflatin and salermide caused increased levels of histone H4 acetylation in zebrafish larvae. Conclusions Our results provide novel, effective methods for performing a combination of small-molecule screen in zebrafish. Our results also add to the growing evidence that epigenetic small molecules may be promising candidates for treating DMD.
Databáze: OpenAIRE
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