DREAM SIGNED

Project "DREAM" data sheet

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 Partnership

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 Project objective

Facioscapulohumeral muscular dystrophy (FSHD) is the most prevalent muscle disease that indiscriminately afflicts children and adults of all ages and both sexes. Despite several clinical trials, there continues to be no cure or therapeutic option available to FSHD patients. FSHD is caused by aberrant myogenic expression of the transcription factor double homeobox 4 (DUX4). In healthy subjects, DUX4 expression is restricted to stem cells and early stages of embryogenesis while being silenced in most tissues of the body. In FSHD, DUX4 mis-expression activates a pro-apoptotic transcriptional program leading to muscle wasting. Compelling data obtained in our laboratory identified MATR3 as the first direct DUX4 inhibitor and a therapeutic molecule. The identification of a novel regulator of DUX4 function now allows us to examine the potential of inhibiting the cytotoxic activity of DUX4 as a therapeutic strategy to treat FSHD, and represents the innovation of this proposal. The goal of the proposal is to fully elucidate the molecular mechanism through which MATR3 regulates DUX4 function in order to develop novel therapeutic approaches for blocking the aberrant activity of DUX4 in FSHD. Based on our preliminary data, I hypothesize that MATR3 protects from DUX4-induced toxicity by inhibiting DUX4 binding to target loci with the end result of preventing transcriptional activation of genes toxic to muscle cells. Characterizing MATR3 mechanism of action will provide possible therapeutic tools that we will evaluate in relevant models of FSHD. As a corollary, we propose that a peptidomimetic molecule representing the DUX4 interacting domain of MATR3 could be used to prevent the toxic effects of DUX4 expression in muscle cells from FSHD patients. This work is significant as it will clarify the molecular pathogenesis of the disease and bring us closer to a rational treatment to block muscle degeneration in FSHD.