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Seminar Davide Gabellini : FSHD muscular dystrophy molecular pathogenesis and therapeutic perspectives

28 février 2020, de 12h à 13h30, amphithéâtre Babinski
Entrée libre et sans inscription

Davide Gabellini, PhD (Head of Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milano, Italy)

Guess: Sestina Falcone

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders. The disease is caused by aberrant gain of expression of the transcription factor DUX4. There is currently no cure or treatment available for FSHD patients. DUX4 is normally expressed at the cleavage stage of early embryonic development in which it plays a key role in the initial activation of the zygotic genome required for implantation. It is subsequently turned off and its expression remain silent in most somatic tissues, including skeletal muscle. In FSHD, due to loss of epigenetic silencing, DUX4 expression is reactivated, which is toxic to skeletal muscle leading to disease. Beside FSHD, aberrant DUX4 reactivation has been reported also in a variety of solid cancers, in which DUX4 mediates immune evasion. Finally, chimeric versions of DUX4 due to genomic translocations drive tumor formation in sarcomas and acute lymphoblastic leukemia.

Thus, inhibitors of DUX4 expression or activity would be relevant not only for FSHD but also for DUX4-associated cancer. Here, I will summarize how, through a series of screenings, we identified the first druggable epigenetic activator of DUX4 gene expression and the first direct inhibitor of DUX4 activity.

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