Abstract
Both genetic types of facioscapulohumeral muscular dystrophy (FSHD) are caused by the pathogenic expression of the homeobox transcription factorDUX4. Aberrant DUX4 expression in maturing myofibers leads to death and the replacement of muscle with fat. DUX4 expression results in profound transcriptional dysregulation and a characteristic DUX4-regulated signature has been described by many laboratories. Clinical evaluation of the p38α/β inhibitor losmapimod is planned where target engagement and inhibition of DUX4 will be measured in muscle biopsies. Reliable detection of DUX4 protein and mRNA in FSHD subject skeletal muscle biopsies is challenging. Instead RNA-seq profiling of FSHD skeletal muscle biopsies was conducted to identify a transcriptional signature indicative of DUX4 expression and activity measurable in losmapimod clinical trials. The design and conceptual framework for selection of a biomarker of DUX4 activity in losmapimod FSHD Phase 2 clinical trials will be presented.
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