期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 28, 页码 16509-16515出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1909649117
关键词
facioscapulohumeral muscular dystrophy; DUX4; LNA gapmers; antisense therapy; FLExDUX4 mouse model
资金
- FSH Society
- Muscular Dystrophy Canada
- University of Alberta
- Women and Children's Health Research Institute
- Friends of FSH Research
- FSHD Global Research Foundation
- Friends of Garrett Cumming Research Fund
- HM Toupin Neurological Science Research Fund
- Canadian Institutes of Health Research
- Canada Foundation for Innovation
- Alberta Enterprise and Advanced Education
Facioscapulohumeral muscular dystrophy (FSHD), characterized by progressive muscle weakness and deterioration, is genetically linked to aberrant expression of DUX4 in muscle. DUX4, in its full-length form, is cytotoxic in nongermline tissues. Here, we designed locked nucleic acid (LNA) gapmer antisense oligonucleo-tides (AOs) to knock down DUX4 in immortalized FSHD myoblasts and the FLExDUX4 FSHD mouse model. Using a screening method capable of reliably evaluating the knockdown efficiency of LNA gapmers against endogenous DUX4 messenger RNA in vitro, we demonstrate that several designed LNA gapmers selectively and effectively reduced DUX4 expression with nearly complete knock-down. We also found potential functional benefits of AOs on mus-cle fusion and structure in vitro. Finally, we show that one of the LNA gapmers was taken up and induced effective silencing of DUX4 upon local treatment in vivo. The LNA gapmers developed here will help facilitate the development of FSHD therapies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据