期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 22, 期 -, 页码 1191-1199出版社
CELL PRESS
DOI: 10.1016/j.omtn.2020.10.028
关键词
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资金
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London
- Wellcome Trust [105604/Z/14/Z]
- NIHR GOSH BRC
- FHSD Society [FSHS-22018-02]
- Association Francaise contre les Myopathies (AFM-Telethon), France [22582]
- Wellcome Trust [105604/Z/14/Z] Funding Source: Wellcome Trust
y Facioscapulohumeral dystrophy (FSHD) is characterized by a loss of repressive epigenetic marks leading to the aberrant expression of the DUX4 transcription factor. In muscle, DUX4 acts as a poison protein though the induction of multiple downstream genes. So far, there is no therapeutic solution for FSHD. Because DUX4 is a transcription factor, we developed an original therapeutic approach, based on a DNA decoy trapping the DUX4 protein, preventing its binding to genomic DNA and thereby blocking the aberrant activation of DUX4's transcriptional network. In vitro, transfection of a DUX4 decoy into FSHD myotubes reduced the expression of the DUX4 network genes. In vivo, both double-stand DNA DUX4 decoys and adeno-associated viruses (AAVs) carrying DUX4 binding sites reduced transcriptional activation of genes downstream of DUX4 in a DUX4-expressing mouse model. Our study demonstrates, both in vitro and in vivo, the feasibility of the decoy strategy and opens new avenues of research.
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