by FRAN SVERDRUP, PHD
St. Louis, Missouri
DUX4 is considered to be a key cause of muscle degeneration in FSH muscular dystrophy. This is why we are interested in finding drugs that “turn off” the production of DUX4, which would prevent the many detrimental activities of this toxic protein. Such drugs would potentially provide the first treatment option for slowing or stopping disease progression in FSHD.
By screening drug libraries in FSHD cells grown in the laboratory, we have identified two classes of drugs that turn off DUX4. One class are drugs that inhibit bromodomain and extra-terminal (BET) proteins, and the second are drugs that turn on beta adrenergic signaling (beta agonists). BET inhibitors are in clinical trials for cancer and other diseases, while beta agonists are widely used for asthma and chronic obstructive pulmonary disease.
These discoveries are important for two reasons. First, we can now explore the potential utility of these drug classes in directly treating FSHD. This is a very exciting prospect, but one that must be viewed with caution because significantly more work must be done before we can determine if these potential drugs would be safe and effective.
An equally exciting prospect is that studying how these drugs turn off DUX4 is likely to uncover additional drug targets. While the research we have published is preliminary, it raises hope that we will be able to treat FSHD with drugs that prevent or even reverse disease progression.
Editor’s note: This research received seed funding from the FSH Society, and was subsequently supported by NIH/NIAMS grant R01AR045203 (SJT); NIH/NINDS grant P01NS069539 (RT, SMvdM, SJT, FMS); NIH training grants T32CA009657 (AEC), T32GM007270 (SCS), and T32HG00035 (SCS); Friends of FSH Research (SJT); FSHD Canada Foundation (YH); Prinses Beatrix Spierfonds grant W.OP14-01 (SMvdM); and Spieren voor Spieren (SMvdM).
Campbell AE, Oliva J, Yates MP, Zhong JW, Shadle SC, Snider L, Singh N, Tai S, Hiramuki Y, Tawil R, van der Maarel SM, Tapscott SJ, Sverdrup FM. BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells. Skeletal Muscle. 2017;7:16. doi: 10.1186/s13395-017-0134-x.