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Systemic antisense therapeutics inhibiting DUX4 expression improves muscle function in an FSHD mouse model

View ORCID ProfileNgoc Lu-Nguyen, Alberto Malerba, George Dickson, Linda Popplewell
doi: https://doi.org/10.1101/2021.01.14.426659
Ngoc Lu-Nguyen
1Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK
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  • ORCID record for Ngoc Lu-Nguyen
Alberto Malerba
1Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK
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George Dickson
1Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK
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Linda Popplewell
1Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK
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  • For correspondence: Linda.Popplewell@rhul.ac.uk
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Abstract

Aberrant expression of the double homeobox 4 (DUX4) gene in skeletal muscle causes muscle deterioration and weakness in Facioscapulohumeral Muscular Dystrophy (FSHD). Since the presence of a permissive pLAM1 polyadenylation signal is essential for stabilization of DUX4 mRNA and translation of DUX4 protein, disrupting the function of this structure can prevent expression of DUX4. We and others have shown promising results using antisense approaches to reduce DUX4 expression in vitro and in vivo following local intramuscular administration. Our group has developed further the antisense chemistries, and demonstrate here enhanced in vitro antisense efficacy. The optimal chemistry was conjugated to a cell-penetrating moiety, and for the first time in FSHD research has been systemically administered into a double-transgenic mouse model of FSHD. After four weekly treatments, mRNA quantities of DUX4 and target genes were reduced by 50% that led to a 5% increase in muscle mass, a 52% improvement in in situ muscle strength, and reduction of muscle fibrosis by 17%. Systemic DUX4 inhibition also improved the locomotor activity significantly and reduced the fatigue level by 22%. Our data overall demonstrate that the optimized antisense approach can contribute to future development of a therapeutic strategy for FSHD.

Competing Interest Statement

A patent named 'Antisense oligonucleotides and uses thereof' has been filed by Royal Holloway University of London, UK and Institute of Myology, Paris, France. L.P. and G.D. are named inventors. The other authors have declared that no conflict of interest exists.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 16, 2021.
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Systemic antisense therapeutics inhibiting DUX4 expression improves muscle function in an FSHD mouse model
Ngoc Lu-Nguyen, Alberto Malerba, George Dickson, Linda Popplewell
bioRxiv 2021.01.14.426659; doi: https://doi.org/10.1101/2021.01.14.426659
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Systemic antisense therapeutics inhibiting DUX4 expression improves muscle function in an FSHD mouse model
Ngoc Lu-Nguyen, Alberto Malerba, George Dickson, Linda Popplewell
bioRxiv 2021.01.14.426659; doi: https://doi.org/10.1101/2021.01.14.426659

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