Mariot, V;
Joubert, R;
Marsollier, A-C;
Hourde, C;
Voit, T;
Dumonceaux, J;
(2020)
A Deoxyribonucleic Acid Decoy Trapping DUX4 for the Treatment of Facioscapulohumeral Muscular Dystrophy.
Molecular Therapy - Nucleic Acids
, 22
pp. 1191-1199.
10.1016/j.omtn.2020.10.028.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | A Deoxyribonucleic Acid Decoy Trapping DUX4 for the Treatment of Facioscapulohumeral Muscular Dystrophy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.omtn.2020.10.028 |
| Publisher version: | https://doi.org/10.1016/j.omtn.2020.10.028 |
| Language: | English |
| Additional information: | a 2020 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | FSHD; Facioscapulohumeral dystrophy; DUX4; Therapy; Muscle; Decoy; Neuromuscular disease |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10126272 |
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