UMMS Affiliation

Department of Cell and Developmental Biology; Department of Neurology; Wellstone Center for FSHD

Publication Date

2016-08-01

Document Type

Article

Disciplines

Animal Experimentation and Research | Cell Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Developmental Biology | Molecular Biology | Molecular Genetics | Musculoskeletal Diseases | Musculoskeletal, Neural, and Ocular Physiology | Nervous System Diseases | Nucleic Acids, Nucleotides, and Nucleosides | Therapeutics

Abstract

Derepression of DUX4 in skeletal muscle has emerged as a likely cause of pathology in facioscapulohumeral muscular dystrophy (FSHD). Here we report on the use of antisense phosphorodiamidate morpholino oligonucleotides to suppress DUX4 expression and function in FSHD myotubes and xenografts. The most effective was phosphorodiamidate morpholino oligonucleotide FM10, which targets the polyadenylation signal of DUX4. FM10 had no significant cell toxicity, and RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Electroporation of FM10 into FSHD patient muscle xenografts in mice also down-regulated DUX4 and DUX4 targets. These findings demonstrate the potential of antisense phosphorodiamidate morpholino oligonucleotides as an FSHD therapeutic option.

Rights and Permissions

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

DOI of Published Version

10.1038/mt.2016.111

Source

Mol Ther. 2016 Aug;24(8):1405-11. doi: 10.1038/mt.2016.111. Epub 2016 Jun 3. Link to article on publisher's site.

Journal/Book/Conference Title

Molecular therapy : the journal of the American Society of Gene Therapy

Related Resources

Link to Article in PubMed

PubMed ID

27378237

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

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