Advances in the molecular understanding of facioscapulohumeral muscular dystrophy (FSHD) have revealed that FSHD results from epigenetic de-repression of the DUX4 gene in skeletal muscle, which encodes a transcription factor that is active in early embryonic development but is normally silenced in almost all somatic tissues. These advances also led to the identification of targets for disease-altering therapies for FSHD, as well as an improved understanding of the molecular mechanism of the disease and factors that influence its progression. Together, these developments led the FSHD research community to shift its focus towards the development of disease-modifying treatments for FSHD. This Review presents advances in the molecular and clinical understanding of FSHD, discusses the potential targeted therapies that are currently being explored, some of which are already in clinical trials, and describes progress in the development of FSHD-specific outcome measures and assessment tools for use in future clinical trials.
Facioscapulohumeral muscular dystrophy (FSHD), a disorder for which there currently is no cure, is characterized by muscle weakness, predominantly affecting muscles in the face, shoulder girdle and upper arms.
FSHD is associated with epigenetic de-repression of the DUX4 gene, which leads to aberrant expression of the transcription factor DUX4 and cytotoxicity in skeletal muscle cells.
Clinical disease progression occurs in a nonlinear and muscle-by-muscle fashion with phases of muscle inflammation preceding rapid fatty replacement of muscle tissue and muscle wasting.
Consensus has been reached on the pathogenetic mechanism of FSHD, and the field is entering a new era of targeted therapy development.
Disease-altering therapies currently in development range from proof-of-principle gene-editing technologies focusing on reducing DUX4 expression to clinical trials of DUX4-blocking agents.
Clinical trials in FSHD require the development of meaningful patient outcome measures, identification of reliable biomarkers and accurate methods of measuring disease progression, such as MRI and ultrasonography.
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The authors apologize to those whose work was not cited or insufficiently cited because of size constraints. Our work is supported by the Prinses Beatrix Spierfonds (W.OR19-06, W.OR21-04), public–private partnerships allowances made available by Health-Holland, Top Sector Life Sciences and Health, The Netherlands, the Medical Research Council UK, Stichting Spieren voor Spieren, the National Institute of Neurological Disorders and Stroke (Grant No. P01NS069539) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant No. P50AR065139). Some of the authors are members of the Radboud University Medical Centre (UMC), Center of Expertise for Neuromuscular Disorders (Radboud-NMD), Netherlands Neuromuscular Center (NL-NMD) and the European Reference Network for Rare Neuromuscular Diseases [ERN EURO-NMD].
K.M. declares that she has acted as a consultant for Avidity Biosciences. S.J.T. declares that he has acted as a consultant for Avidity Biosciences and is a Board member for Renogenyx. R.T. declares that he has acted as a consultant and/or is a member of the advisory board for Arrowhead Pharma, Avidity Biosciences, Dyne Therapeutics, Fulcrum Therapeutics, Mitsubishi Tanabe Pharma, miRecule Biotech and Roche. J.M.S. declares that he has acted as a consultant and/or is a member of the advisory board for Acceleron, Avidity Biosciences, Dyne Therapeutics, Fulcrum Therapeutics, Ionis, ML Bio Solutions, Mitsubishi Tanabe Pharma, Roche and Sarepta. S.M.v.d.M. declares that he has acted as consultant and/or is a member of the advisory board for Avidity Biosciences, Dyne Therapeutics and Fulcrum Therapeutics and is a Board member for Renogenyx. The other authors declare no competing interests.
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Spreading of epigenetic chromatin modifications from a locus to neighbouring loci on the same chromatin strand.
- FSHD Composite Outcome Measure
(FSHD-COM) An evaluator-administered instrument composed of individually validated functional motor tasks that assess leg, shoulder and arm, trunk and hand function and balance.
- FSHD Health Index
(FSHD-HI) A patient-reported outcome measures to assess total FSHD health-related quality of life and 14 separate subdomains, each identified by FSHD patients as having the greatest importance to their specific population.
- FSHD-Rasch-built Overall Disability Scale
(FSHD-RODS) A linear-weighted patient-reported outcome measure for detecting activity and participation restrictions in patients with FSHD.
- PAX7 score
The ratio of genes induced to genes repressed indicated by the satellite cell marker PAX7, which is closely related to DUX4.
Lasting target gene expression followed after a short DUX4 transcriptional burst.
A DNA region flanking the most distal D4Z4 unit that contains the polyadenylation signal (PAS) of the DUX4 gene, named after the cosmid clone used for its isolation.
- Proximity ligation assay
An antibody assay based on rolling-circle amplification of a DNA loop formed from ligation of oligonucleotide-labelled probes bound to distinct primary antibodies, used for detection of proteins at single-molecule resolution in unmodified cells and tissues.
- Pseudotime trajectory modelling
A computational method used in single-cell transcriptomics to establish the pattern of a dynamic cellular process; followed by ordering of cells based on their progression through the process.
- Reachable Workspace
(RWS) A depth-ranging sensor (Kinect)-based upper extremity motion analysis system that is applied to determine the spectrum of reachable workspace encountered with the arms and shoulders.
A segment of DNA reverse-transcribed from mRNA and randomly inserted into a genome.
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Tihaya, M.S., Mul, K., Balog, J. et al. Facioscapulohumeral muscular dystrophy: the road to targeted therapies. Nat Rev Neurol 19, 91–108 (2023). https://doi.org/10.1038/s41582-022-00762-2