Derepression of DUX4 in skeletal muscle has emerged as a likely cause of pathology in facioscapulohumeral muscular dystrophy (FSHD). Here, the authors describe a proof-of-concept study of the therapeutic potential of antisense phosphorodiamidate morpholino oligonucleotides (PMOs) for the treatment of FSHD, by targeting DUX4 and demonstrating efficacy in both FSHD myogenic cells and human muscle xenografts. The most effective was PMO FM10, which targets the polyadenylation signal of DUX4. FM10 had no significant cell toxicity, and RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Electroporation of FM10 into FSHD patient muscle xenografts in mice also down-regulated DUX4 and DUX4 targets. These findings demonstrate the potential of antisense PMOs as an FSHD therapeutic option.
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Chen JC, King OD, Zhang Y, et al. Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Mol Ther. 2016 Jul 5. doi: 10.1038/mt.2016.111. [Epub ahead of print]
