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The study titled "Modulators of Epigenetic Disease" will use recent advances in understanding the cause of FSHD to develop resources that can be used to identify drugs or other agents that might improve or cure FSHD. Prior work funded by Friends of FSH Research has identified the expression of a gene called DUX4 as the cause of FSHD, and ongoing studies are identifying how the activity of DUX4 might damage the muscle cells. This new project, funded by Friends of FSH Research, will develop cells that can be easily monitored for DUX4 activity and show that these cells can be used to identify drugs that would be candidate treatments for FSHD. This will be an important step toward attracting the interest of pharmaceutical companies and developing a treatment for FSHD that can be advanced into clinical trials.
Co-PI: Joel Chamberlain PhD
The milestones for year one were to perform an initial screen for Platform 1 and prepare and validate Platform 2.
Expressing DUX4 in muscle cells results in cell death. Therefore agents that prevent cell death have therapeutic potential. Screening for agents that facilitate survival of DUX4 expressing cells might yield relatively non-specific agents, but is an efficient way to quickly prioritize agents for more specific screens. We evaluated three cell types for DUX4 induced toxicity. We determined a time course of death and percentage of death following DUX4 induction and identified a cell line that had a highly reproducible profile suitable for high throughput screening. The format used and the cell death assay met the criteria for the Genomics Shared Resource Screening Facility to initiate the screen; however, the method of DUX4 induction did not. Therefore, we sought to develop an inducible construct that would satisfy the requirement of the screening facility. Although we thought our new strategy to produce the inducible construct was rather straightforward, it proved much more difficult than we had anticipated. However, at this point we do not anticipate any further problems with preparing the cells for the Genomics facility.
We currently believe that any intervention that blocks the activity of the DUX4 transcription factor will be a candidate therapeutic for FSHD. Our recent work has identified genes regulated by DUX4 and the DUX4 binding regions that transcriptionally activate these genes. We have made a construct that uses the regulatory elements from one of the DUX4 regulated genes to drive expression of the luciferase reporter gene and demonstrated that this construct shows robust activation by DUX4. The next step is to introduce this construct into FSHD cells. We have made substantial progress on cloning and validating additional DUX4 responsive promoters and now have several candidate second or third reporter genes that can be co-introduced into cells.
See resulting paper published in PLOS Genetics.