ArticleThe Journal of clinical investigation2019
Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 70 citations in OpenAlex.
- The neuropathy-causingbioRxiv : the preprint server for biology · 2026Article
- Safety, efficacy, and distal nerve Schwann cell biodistribution in mice and NHPs to support translation of AAV9 RNAi therapy for CMT1A.Molecular therapy. Nucleic acids · 2026Article
- Development ofMolecular therapy. Advances · 2026Article
- Review
- Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- Aminoacyl-tRNA Synthetases: Variant Classification, Functional Assays, and Emerging Therapeutic Strategies.Journal of inherited metabolic disease · 2026Review
- AAV-Delivered RNAi Targeting Mutant LDB3 Prevents and Reverses Myofibrillar Myopathy through Mechanosignaling Restoration.bioRxiv : the preprint server for biology · 2026Article
- The Neuromuscular Junction: A Shared Vulnerability in Aging and Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Review
- SARM1 Inhibition in Three Mouse Models of Charcot-Marie-Tooth Disease.Journal of the peripheral nervous system : JPNS · 2025Article
- Evaluating the feasibility of gene replacement strategies to treat MTRFR deficiency.Disease models & mechanisms · 2025Article
- Developing a gene therapy for Charcot-Marie-Tooth disease: progress and challenges.Regenerative medicine · 2025Review
- Glycyl-tRNA sequestration is a unifying mechanism underlying GARS1-associated peripheral neuropathy.Nucleic acids research · 2025Article
- Evaluation of the Role of Tanshinone I in an In Vitro System of Charcot-Marie-Tooth Disease Type 2N.International journal of molecular sciences · 2024Article
- Current Treatment Methods for Charcot-Marie-Tooth Diseases.Biomolecules · 2024Review
- Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches.International journal of molecular sciences · 2024Review
- A model organism pipeline provides insight into the clinical heterogeneity of TARS1 loss-of-function variants.HGG advances · 2024Article
- Optimized allele-specific silencing of the dominant-negativeMolecular therapy. Nucleic acids · 2024Article
- Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy.Neurobiology of disease · 2024Article
- Lack of effect from genetic deletion of Hdac6 in a humanized mouse model of CMT2D.Journal of the peripheral nervous system : JPNS · 2024Article
- Molecular mechanisms and therapeutic strategies for neuromuscular diseases.Cellular and molecular life sciences : CMLS · 2024Review
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Authors and funding
23 authors at 7 institutions in 1 country.
Funding
Abstract
Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3-4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases.
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