Systemic antisense therapeutics inhibiting DUX4 expression ameliorates FSHD-like pathology in an FSHD mouse model. / Lu-Nguyen, Ngoc; Malerba, Alberto; Herath, Shan; Dickson, George; Popplewell, Linda.

In: Human Molecular Genetics, 13.05.2021.

Research output: Contribution to journalArticlepeer-review

E-pub ahead of print


  • Accepted Manuscript

    Accepted author manuscript, 1.54 MB, PDF document

    Embargo ends: 13/05/22


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. Here we demonstrate that further development of the antisense chemistries enhances in vitro antisense efficacy. The optimal chemistry was conjugated to a cell-penetrating moiety and was systemically administered into the tamoxifen-inducible Cre-driver FLExDUX4 double-transgenic mouse model of FSHD. After four weekly treatments, mRNA quantities of DUX4 and target genes were reduced by 50% that led to 12% amelioration in muscle atrophy, 52% improvement in in situ muscle strength, 17% reduction in muscle fibrosis, and prevention of shift in the myofiber type profile. Systemic DUX4 inhibition also significantly improved the locomotor activity and reduced the fatigue level by 22%. Our data demonstrate that the optimized antisense approach has potential of being further developed as a therapeutic strategy for FSHD.

Original languageEnglish
Article numberddab136
JournalHuman Molecular Genetics
Early online date13 May 2021
Publication statusE-pub ahead of print - 13 May 2021
This open access research output is licenced under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

ID: 42133700