Development of anti-DUX4 therapeutics for FSHD

DESCRIPTION (provided by applicant): FSHD affects over 25,000 individuals in the United States. It is the third most common muscular dystrophy by incidence but may be the most common by prevalence (Orphanet, 2008). The disease is thought to be caused by a combination of chromatin changes that cause expression of the DUX4 gene, together with stabilization of the DUX4 transcript by an allele-specific polyA signal. Pharmacological inhibition of DUX4 activity is an attractive approach to developing a therapy for FSHD. We have shown that DUX4 causes cell death of C2C12 myoblasts, used this assay to screen 200,000 compounds for inhibitors of DUX4, performed a number of secondary screens, and identified approximately 640 verified hits. From this set, we propose to identify those compounds with the highest likelihood of being developed into drugs. We will begin preliminary preclinical development by synthesizing key compounds and related derivatives, and screening these for activity on DUX4-expressing cells. We will test the most promising of these in mouse models based on conditional expression of DUX4. We aim to identify 1-3 chemical series suitable for continued development into drugs for the treatment of FSHD.