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Facioscapulohumeral muscular dystrophy (FSHD) is a gain-of-function genetic disorder caused by the loss of repressive epigenetic marks at the D4Z4 macrosatellite repeat array on chromosome 4q35. This epigenetic relaxation, when combined with a permissive 4q distal haplotype, defines the FSHD-permissive allele. Its transcription leads to the aberrant expression in skeletal muscle of the double homeobox transcription factor DUX4 (a gene normally confined to the earliest stages of embryogenesis), disrupting muscle homeostasis and triggering progressive degeneration. Over the past decade, extensive genetic and mechanistic studies have transformed the FSHD landscape. Despite the different genetic causes and the mosaic, temporally sporadic, spatially restricted nature of FSHD, a unified genetic model has emerged. Although the exact role of DUX4 in disease pathogenesis remains to be fully deciphered, a substantial body of evidence implicates it as the central driver of pathology. It is therefore an appealing therapeutic target, and several clinical trials are now underway to determine if suppressing its expression or activity is therapeutic. One of the current challenges in assessing these therapies is the identification of biomarkers capable of capturing disease activity, severity, and target engagement. This is especially challenging with a disease, like FSHD, that progresses slowly and heterogeneously. Progress in identifying biomarkers for potential clinical use marks a turning point for FSHD studies that can pave the way for therapies targeting the root cause of the disease. Here, we integrate what is known about the genetic and epigenetic mechanisms of DUX4 derepression with emerging evidence for spatiotemporal DUX4 toxicity in muscle. We argue that the mosaic expression of DUX4 has direct consequences for the design of biomarkers, the selection of biopsy muscles and sampling sites, and the appropriate endpoints in clinical trials. Finally, we outline a pragmatic approach to align DUX4-targeted and downstream therapies with biomarker strategies that are realistic for FSHD trial design.
Mariot et al. (Tue,) studied this question.