GRANT 27

The main goal of this study was to evaluate two compounds, fisetin and VBP15, as potential treatments of FSHD. After we discovered that both compounds suppressed DUX4 expression in muscle cells from patients, we investigated the effects of these compounds in vivo using an FSHD mouse model. In our studies, we first determined dosages and methods of delivery of these compounds. We identified an effective dosage and delivery route for VBP15. In addition, our data suggested that VBP15 promoted muscle repair/regeneration activities in the mice. Our data from fisetin studies indicated that the delivery strategy for fisetin needed modification in order for fisetin to reach an effective level in vivo. One of the challenges of using the current mouse model is that DUX4 expression level is low, which makes it difficult to study agents that suppress expression of DUX4. Therefore, we have been searching for a better FSHD mouse model for the proposed studies. Recently, we have identified a new model which expresses DUX4 at higher level and can be adjusted as needed, therefore ideal for studying DUX4 suppression in vivo. Our next steps include developing better in vivo delivery strategies for fisetin; determining long term benefit of VBP15 in vivo; and testing both fisetin and VBP15 in the new FSHD