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FSHD occurs when muscle produces a protein that should not be present in muscle, the DUX4 protein. Inactivating the DUX4 protein is therefore the most feasible way to treat the disease. Over the past several years, we have been engaged in studies to identify small molecules that block the activity of the DUX4 protein. Although we have had success identifying compounds that protect cells from the effects of DUX4, it has proven challenging to find small molecules that bind to and inhibit the activity of the DUX4 protein. For theoretical reasons, because of the type of protein that DUX4 is (a transcription factor), such inhibitors tend not to be present within the collections of chemical compounds that have been available for such studies. For theoretical reasons, larger and much more complex chemicals are better inhibitors of such proteins.
An exciting new technology has recently been established to discover such compounds by performing genetic selection either in mammalian cells or in bacterial strains modified to carry the protein of interest, and a large “library” of different minigenes, each of which encodes a different complex molecule. With the appropriate selection system, a only cell that carries the gene encoding a potent inhibitory molecule will survive, and by sequencing this gene, we can determine what that molecule is. We will use this approach to discover molecules that bind to and inhibit the activity of the DUX4 protein. We expect this approach to lead to candidates for drugs to treat FSHD.