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Inhibition of DUX4 expression with antisense LNA gapmers as a therapy for facioscapulohumeral muscular dystrophy.


ABSTRACT: 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 oligonucleotides (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 knockdown. We also found potential functional benefits of AOs on muscle 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.

SUBMITTER: Lim KRQ 

PROVIDER: S-EPMC7368245 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Inhibition of <i>DUX4</i> expression with antisense LNA gapmers as a therapy for facioscapulohumeral muscular dystrophy.

Lim Kenji Rowel Q KRQ   Maruyama Rika R   Echigoya Yusuke Y   Nguyen Quynh Q   Zhang Aiping A   Khawaja Hunain H   Sen Chandra Sreetama S   Jones Takako T   Jones Peter P   Chen Yi-Wen YW   Yokota Toshifumi T  

Proceedings of the National Academy of Sciences of the United States of America 20200629 28


Facioscapulohumeral muscular dystrophy (FSHD), characterized by progressive muscle weakness and deterioration, is genetically linked to aberrant expression of <i>DUX4</i> in muscle. DUX4, in its full-length form, is cytotoxic in nongermline tissues. Here, we designed locked nucleic acid (LNA) gapmer antisense oligonucleotides (AOs) to knock down <i>DUX4</i> in immortalized FSHD myoblasts and the <i>FLExDUX4</i> FSHD mouse model. Using a screening method capable of reliably evaluating the knockdo  ...[more]

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