Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 25, Issue -, Pages 342-354Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2021.05.020
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Funding
- Friends of FSH Research
- Prinses Beatrix Spierfonds [W.OP14-01, W.OR21-04]
- Spieren voor Spieren
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This study presents a strategy for mutagenesis of the somatic DUX4 polyadenylation signal using adenine base editing in immortalized myoblasts from FSHD-affected individuals, leading to downregulation of DUX4 mRNA and its target genes. These findings highlight the potential therapeutic target of the somatic DUX4 polyadenylation signal and represent the initial step towards clinical application of the CRISPR-Cas9 base editing platform for FSHD gene therapy.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by chromatin relaxation of the D4Z4 repeat resulting in misexpression of the D4Z4-encoded DUX4 gene in skeletal muscle. One of the key genetic requirements for the stable production of full-length DUX4 mRNA in skeletal muscle is a functional polyadenylation signal (ATTAAA) in exon three of DUX4 that is used in somatic cells. Base editors hold great promise to treat DNA lesions underlying genetic diseases through their ability to carry out specific and rapid nucleotide mutagenesis even in postmitotic cells such as skeletal muscle. In this study, we present a simple and straightforward strategy for mutagenesis of the somatic DUX4 polyadenylation signal by adenine base editing in immortalized myoblasts derived from independent FSHD-affected individuals. We show that mutating this critical cis-regulatory element results in downregulation of DUX4 mRNA and its direct transcriptional target genes. Our findings identify the somatic DUX4 polyadenylation signal as a therapeutic target and represent the first step toward clinical application of the CRISPR-Cas9 base editing platform for FSHD gene therapy.
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