PUBLICATION

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

Authors
Farr, G.H., Morris, M., Gomez, A., Pham, T., Kilroy, E., Parker, E.U., Said, S., Henry, C., Maves, L.
ID
ZDB-PUB-201020-22
Date
2020
Source
Skeletal muscle   10: 29 (Journal)
Registered Authors
Farr III, G. Hank, Henry, Clarissa A., Maves, Lisa
Keywords
Chemical screen, Duchenne muscular dystrophy, Epigenetic small molecules, HDAC inhibitors, Zebrafish
MeSH Terms
  • Membrane Proteins/genetics
  • Naphthols/pharmacology
  • Epigenesis, Genetic
  • Small Molecule Libraries/pharmacology*
  • Muscle, Skeletal/drug effects*
  • Muscle, Skeletal/metabolism
  • Zebrafish
  • Phenylpropionates/pharmacology
  • Animals
  • High-Throughput Screening Assays
  • Muscular Dystrophy, Duchenne/drug therapy*
  • Muscular Dystrophy, Duchenne/genetics
  • Cells, Cultured
  • Drug Discovery
  • Hydroxamic Acids/pharmacology
  • Muscle Proteins/genetics
  • Zebrafish Proteins/genetics
  • Histone Deacetylase Inhibitors/pharmacology*
(all 18)
PubMed
33059738 Full text @ Skelet Muscle
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. 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.
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.
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.
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.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
No data available
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ta222a
    Point Mutation
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    No data available
    Fish
    1 - 1 of 1
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    Antibodies
    Name Type Antigen Genes Isotypes Host Organism
    Ab1-dmdmonoclonalIgG1Mouse
    Ab5-h4polyclonal
      IgGRabbit
      Ab10-h4polyclonal
        IgGRabbit
        1 - 3 of 3
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        Orthology
        No data available
        Engineered Foreign Genes
        No data available
        Mapping
        No data available