Facioscapulohumeral muscular dystrophy (FSHD) represents one of the most prevalent neuromuscular disorder afflicting 1/8000 individuals. Weakness is slowly progressive with high variability among patients. Unfortunately, despite life expectance is not modified, affected individuals eventually requires a wheelchair. FSHD is caused by aberrant re-activation of the transcription factor DUX4, which is physiological restricted in the early stage of embryo development. In FSHD, DUX4 mis-expression initiates a cascade of processes triggering the activation of a pro-apoptotic transcriptional program leading to muscle wasting. DUX4 has been recently implicated also in the pathogenesis of solid tumors, leukemia and herpes viral infection. As today, no cure or therapeutic option are available to FSHD patients. Given its pivotal role in FSHD, blocking DUX4 activity is a plausible therapeutic option for FSHD and other diseases associated with aberrant DUX4 expression or activity.
Compelling data obtained in our laboratory identified a novel regulator of DUX4 that allows us to examine the potential of inhibiting the cytotoxic activity of DUX4 as a therapeutic strategy to treat FSHD, and represented the innovation of this proposal. The goal of the proposal was to fully elucidate the molecular mechanisms that regulate DUX4 in order to develop novel therapeutic approaches for blocking the aberrant activity of DUX4 in FSHD.
Based on our preliminary data, I hypothesized that by inhibiting DUX4 we can prevent transcriptional activation of genes toxic to muscle cells.
As a corollary, we proposed that a drug-like molecule interfering with the DUX4 pathway could be used to prevent the toxic effects of DUX4 expression in muscle cells from FSHD patients and animal model of FSHD.
With this project we demonstrated that MATR3 binds directly to DUX4 and blocks its activity. We also mapped the regions involved in the interaction and developed a gene therapy approach based on MATR3. Our results promote MATR3 as the first endogenous inhibitor of DUX4 for the treatment of FSHD that in perspective might be applied to a spectrum of related and currently incurable DUX4-associated diseases.
