Host - Dr Jon Beauchamp
Dr Julie Dumonceaux
University College London
What happens when an ancient DNA retro-element gets activated and comes back to life in error?
Facio-scapulo-humeral muscular dystrophy (FSHD) and new therapeutic approaches.
FSHD is one of the most common muscular dystrophies and so far there is no curative or preventive treatment. FSHD is characterized by a loss of repressive epigenetic marks within the D4Z4 array, leading to chromatin relaxation and, when associated with a permissive chromosome 4, to the expression of the normally silenced DUX4 protein whose ORF is present in each D4Z4 repeat. DUX4 is a transcription factor resulting in a poison protein through induction of downstream genes, which may play a major role in FSHD onset/progression.
Our laboratory has been working on FSHD for years, deciphering the molecular pathways leading to FSHD onset. We have also recently developed different innovative therapeutic strategy for FSHD. The first one aims at targeting the 3’ UTR key elements of DUX4 pre-mRNA using antisense oligonucleotides to inhibit the polyadenylation and induce mRNA degradation. In the second one, a new strategy, never developed for a neuromuscular disease, was evaluated. Because DUX4 is a transcription factor, we designed DNA decoys trapping the DUX4 protein, thereby preventing its binding to genomic DNA. We established proof of principle in vitro for these therapeutic strategies capable of inhibiting DUX4 pathway.