FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?

Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to...

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Bibliographic Details
Published in:Journal of personalized medicine 2022-05, Vol.12 (6), p.865
Main Authors: Himeda, Charis L., Jones, Peter L.
Format: Article
Language:English
Subjects:
Chromatin
Clinical trials
CRISPR
Drug dosages
Epigenetics
FDA approval
Gene expression
Genetic disorders
Genomes
Muscular dystrophy
Musculoskeletal system
Mutation
Oligonucleotides
Precision medicine
Review
Skeletal muscle
Transcription factors
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Summary:Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, pathogenic misexpression of DUX4 in skeletal muscle. The complex nature of the locus and the fact that FSHD is a toxic, gain-of-function disease present unique challenges for the design of therapeutic strategies. There are three major DUX4-targeting avenues of therapy for FSHD: small molecules, oligonucleotide therapeutics, and CRISPR-based approaches. Here, we evaluate the preclinical progress of each avenue, and discuss efforts being made to overcome major hurdles to translation.
ISSN:2075-4426
2075-4426
DOI:10.3390/jpm12060865