Improving molecular and histopathology in diaphragm muscle of the double transgenic ACTA1-MCM/FLExDUX4 mouse model of FSHD with systemic antisense therapy. / Lu-Nguyen, Ngoc; Malerba, Alberto; Antoni Pineda, Marina; Dickson, George; Popplewell, Linda J.

In: Human Gene Therapy, 28.04.2022.

Research output: Contribution to journalArticlepeer-review

E-pub ahead of print


Facioscapulohumeral muscular dystrophy (FSHD) is a rare muscle dystrophy causing muscle weakness initially in the face, shoulders and upper arms, and extended to lower body muscles as the disease progresses. Respiratory restriction in FSHD is increasingly reported to be more common and severe than previously thought, with the involvement of diaphragm weakness in pulmonary insufficiency being under debate. As aberrant expression of the double homeobox 4 (DUX4) gene is the prime cause of FSHD, we and others have developed numerous strategies and reported promising results on downregulating DUX4 expression in both cellular and animal models of FSHD. However, the effect of DUX4 and anti-DUX4 approaches on diaphragm muscle has not been elucidated. Here we show that toxic DUX4 expression causes pathology that affects the diaphragm of ACTA1-MCM/FLExDUX4 mouse model of FSHD at both molecular and histological levels. Of importance, a systemic antisense treatment that suppresses DUX4 and target genes expression by 50% significantly improves muscle regeneration and muscle fibrosis, and prevents modification in myofiber type composition, supporting its development as a treatment for FSHD.

Original languageEnglish
JournalHuman Gene Therapy
Publication statusE-pub ahead of print - 28 Apr 2022
This open access research output is licenced under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

ID: 44454348