ArticleHuman molecular genetics2021
Systemic antisense therapeutics inhibiting DUX4 expression ameliorates FSHD-like pathology in an FSHD mouse model.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 27 citations in OpenAlex.
- The role of mNaunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Lipid nanoparticle delivery of antisense gapmers attenuates pathology in a mouse model of facioscapulohumeral muscular dystrophy.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- RNA Therapeutics Targeting Skeletal Muscle: Emerging Antisense and Gene-Modifying Strategies.Biomolecules · 2026Review
- Development of a DUX4-targeting antibody oligonucleotide conjugate as a therapy for FSHD.Nucleic acids research · 2026Article
- Article
- AAV-shDUX4 provides short-term benefits but limited long-term efficacy in a DUX4 mouse model of FSHD.Molecular therapy. Methods & clinical development · 2025Article
- The recent clinical trial of losmapimod for the treatment of facioscapulohumeral muscular dystrophy.Neuromuscular disorders : NMD · 2025Review
- Temporal variation in p38-mediated regulation of DUX4 in facioscapulohumeral muscular dystrophy.Scientific reports · 2024Article
- Molecular, Histological, and Functional Changes in Acta1-MCM;FLExDUX4/+ Mice.International journal of molecular sciences · 2024Article
- Oligonucleotide Therapies for Facioscapulohumeral Muscular Dystrophy: Current Preclinical Landscape.International journal of molecular sciences · 2024Review
- Systemic Pharmacotherapeutic Treatment of the ACTA1-MCM/FLExDUX4 Preclinical Mouse Model of FSHD.International journal of molecular sciences · 2024Article
- Molecular mechanisms and therapeutic strategies for neuromuscular diseases.Cellular and molecular life sciences : CMLS · 2024Review
- Flavones provide resistance to DUX4-induced toxicity via an mTor-independent mechanism.Cell death & disease · 2023Article
- The endosomal escape vehicle platform enhances delivery of oligonucleotides in preclinical models of neuromuscular disorders.Molecular therapy. Nucleic acids · 2023Article
- A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice.Biomedicines · 2023Article
- Molecular and Phenotypic Changes in FLExDUX4 Mice.Journal of personalized medicine · 2023Article
- Influence ofInternational journal of molecular sciences · 2023Review
- Facioscapulohumeral muscular dystrophy: the road to targeted therapies.Nature reviews. Neurology · 2023Review
- Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases.Pharmaceutics · 2022Review
- Long-Term Systemic Treatment of a Mouse Model Displaying Chronic FSHD-like Pathology with Antisense Therapeutics That InhibitBiomedicines · 2022Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant expression of the double homeobox 4 (DUX4) gene in skeletal muscle causes muscle deterioration and weakness in Facioscapulohumeral muscular dystrophy (FSHD). Since the presence of a permissive pLAM1 polyadenylation signal is essential for stabilization of DUX4 mRNA and translation of DUX4 protein, disrupting the function of this structure can prevent expression of DUX4. We and others have shown promising results using antisense approaches to reduce DUX4 expression in vitro and in vivo following local intramuscular administration. Here we demonstrate that further development of the antisense chemistries enhances in vitro antisense efficacy. The optimal chemistry was conjugated to a cell-penetrating moiety and was systemically administered into the tamoxifen-inducible Cre-driver FLExDUX4 double-transgenic mouse model of FSHD. After four weekly treatments, mRNA quantities of DUX4 and target genes were reduced by 50% that led to 12% amelioration in muscle atrophy, 52% improvement in in situ muscle strength, 17% reduction in muscle fibrosis and prevention of shift in the myofiber type profile. Systemic DUX4 inhibition also significantly improved the locomotor activity and reduced the fatigue level by 22%. Our data demonstrate that the optimized antisense approach has potential of being further developed as a therapeutic strategy for FSHD.
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