Inhibition of <i>DUX4</i> expression with antisense LNA gapmers as a therapy for facioscapulohumeral muscular dystrophy
Kenji Rowel Q. Lim, Rika Maruyama, Yusuke Echigoya, Quynh Nguyen, Aiping Zhang, Hunain Khawaja, Sreetama Sen Chandra, Takako I. Jones, Peter L. Jones, Yi-Wen Chen, Toshifumi Yokota
Abstract
Significance Facioscapulohumeral dystrophy (FSHD) is an inherited disabling muscular disorder caused by misexpression of DUX4 in skeletal muscles. FSHD has variable onset; its infantile form has a more severe disease course. There is no cure for FSHD. Here, we show the potential of antisense oligonucleotides called locked nucleic acid (LNA) gapmers for treating FSHD. We designed LNA gapmers to knock down DUX4 messenger RNA and found that its expression was effectively reduced in patient-derived cells and an FSHD mouse model. Functional benefits and minimal off-targeting were observed in vitro. Our study facilitates progress toward finding new candidates for treating FSHD. The screening protocol used here for antisense oligonucleotides targeting DUX4 can also be adapted by other efforts developing similar treatments for FSHD.