Abstract| Volume 25, SUPPLEMENT 2, S311-S312, October 2015

Antisense strategies targeting DUX4 and DUX4c as therapeutic approaches for facioscapulohumeral muscular dystrophy (FSHD)

      FSHD affects about 1/20,000 individuals and is characterized by progressive skeletal muscle atrophy. FSHD1 (OMIM #158900) is linked to contractions of the D4Z4 repeat array in 4q35 whereas FSHD2 (OMIM #158901) is associated with mutations in SMCHD1, a chromatin modifier. In both FSHD types (i) D4Z4 DNA is hypomethylated, causing chromatin opening and expression of DUX4 (Double homeobox 4) the FSHD causal gene we have identified in D4Z4 elements; (ii) a 4qA permissive allele provides a polyA addition signal to stabilize DUX4 mRNAs. DUX4 is a transcription factor that initiates a large gene deregulation cascade leading to the major FSHD clinical features. The chromatin opening may induce other 4q35 genes such as DUX4c, a DUX4 homolog we have identified that encodes a truncated protein not sharing DUX4 toxicity. FSHD muscle sections reveal small angular atrophic fibers but also hypertrophic fibers and clusters of nuclei. In our primary culture conditions FSHD myoblasts can fuse to myotubes similar to either fiber type: “atrophic” thin and elongated (aFSHD) or large “disorganized” tubes with clusters of nuclei (dFSHD), either type presenting a different proteomic profile. We have shown by gain and loss (siRNA; antisense oligonucleotides) of functions that DUX4 expression induced aFSHD myotubes. DUX4c expression induced differentiation defects involving proteins of the cytoskeleton or the contractile apparatus and nuclear clusters as seen in dFSHD myotubes. This phenotype was only suppressed by antisense agents targeting DUX4c. In aggregate our experiments suggest that besides DUX4, DUX4c should be an additional therapeutic target in FSHD. For lack of an appropriate transgenic mouse model, we performed naked DNA injection into lower limb muscles in the mouse. Two different LacZ reporter expression levels and patterns were found which could both be relevant for FSHD. DUX4/4c expression vectors are being injected to evaluate the specific antisense agents.
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