Department of Cell and Developmental Biology; Department of Neurology; Wellstone Center for FSHD
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
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.
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DOI of Published Version
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.
Molecular therapy : the journal of the American Society of Gene Therapy
Chen JC, King OD, Zhang Y, Clayton NP, Spencer C, Wentworth BM, Emerson CP, Wagner KR. (2016). Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Cell and Developmental Biology Publications. https://doi.org/10.1038/mt.2016.111. Retrieved from https://escholarship.umassmed.edu/cellbiology_pp/196
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This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.
Animal Experimentation and Research Commons, Cell Biology Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Developmental Biology Commons, Molecular Biology Commons, Molecular Genetics Commons, Musculoskeletal Diseases Commons, Musculoskeletal, Neural, and Ocular Physiology Commons, Nervous System Diseases Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons, Therapeutics Commons