ArticleMolecular therapy : the journal of the American Society of Gene Therapy2023
Di-valent siRNA-mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington's disease.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers.
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34 citing papers in PubMed, 52 citations in OpenAlex.
- Fatty-acid-based antimiR-23b delivery in the DMSXL model: A potential therapeutic strategy for brain dysfunction in myotonic dystrophy type 1.Cell reports. Medicine · 2026Article
- Deciphering cell type-specific causal genetic effects on brain imaging-derived phenotypes and disorders with single-cell Mendelian randomization.PLoS computational biology · 2026Article
- Target sequence-conditioned design of peptide binders using masked language modeling.Nature biotechnology · 2026Article
- Expanding repeats, expanding impact: Somatic instability in myotonic dystrophy type 1.Journal of neuromuscular diseases · 2026Review
- ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Review
- Huntington disease: somatic expansion, pathobiology and therapeutics.Nature reviews. Neurology · 2026Review
- Integrative single-nucleus transcriptomic analysis identifies UBE2C+ proliferative tumor cells and immune-stromal regulatory crosstalk in small cell lung cancer.Frontiers in immunology · 2026Article
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Suppression of Huntington's Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding.Nature communications · 2025Article
- Bias in HD-ISS staging introduced by the FreeSurfer cross-sectional stream: Insights from the Huntington's Disease Young Adult Study (HD-YAS).Journal of Huntington's disease · 2025Article
- Myotonic dystrophy type 1: clinical diversity, molecular insights and therapeutic perspectives.Nature reviews. Neurology · 2025Review
- Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid-siRNA conjugate administered into cerebrospinal fluid.Nucleic acids research · 2025Article
- CAG-targeted brain-permeable therapy tested in biallelic humanized polyQ mouse models.Molecular therapy. Nucleic acids · 2025Article
- Interventionally targeting somatic CAG expansions can be a rapid disease-modifying therapeutic avenue: Preclinical evidence.bioRxiv : the preprint server for biology · 2025Article
- Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis.Nature medicine · 2025Observational
- Genetic Diversity and Environmental Adaptation Signatures of the Great Seahorse (International journal of molecular sciences · 2025Article
- When repetita no-longer iuvant: somatic instability of the CAG triplet in Huntington's disease.Nucleic acids research · 2025Review
- Mutant huntingtin exon 1 protein detected in mouse brain with neoepitope antibody: effects of CAG repeat expansion, MutS Homolog 3 silencing and aggregation.Brain communications · 2025Article
- Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of CaMolecular therapy. Nucleic acids · 2024Article
- Structural and Dynamical Properties of Nucleic Acid Hairpins Implicated in Trinucleotide Repeat Expansion Diseases.Biomolecules · 2024Review
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
21 authors at 5 institutions in 1 country.
Funding
Abstract
Huntington's disease (HD) is a severe neurodegenerative disorder caused by the expansion of the CAG trinucleotide repeat tract in the huntingtin gene. Inheritance of expanded CAG repeats is needed for HD manifestation, but further somatic expansion of the repeat tract in non-dividing cells, particularly striatal neurons, hastens disease onset. Called somatic repeat expansion, this process is mediated by the mismatch repair (MMR) pathway. Among MMR components identified as modifiers of HD onset, MutS homolog 3 (MSH3) has emerged as a potentially safe and effective target for therapeutic intervention. Here, we identify a fully chemically modified short interfering RNA (siRNA) that robustly silences Msh3 in vitro and in vivo. When synthesized in a di-valent scaffold, siRNA-mediated silencing of Msh3 effectively blocked CAG-repeat expansion in the striatum of two HD mouse models without affecting tumor-associated microsatellite instability or mRNA expression of other MMR genes. Our findings establish a promising treatment approach for patients with HD and other repeat expansion diseases.
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