ArticleProceedings of the National Academy of Sciences of the United States of America2012
Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
98 citing papers in PubMed, 1 synthesis or guideline pooled it, 189 citations in OpenAlex.
- Gene Therapy Advances: A Meta-Analysis of AAV Usage in Clinical Settings.Frontiers in medicine · 2021Pooled it
- Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: A first-in-human study.British journal of clinical pharmacology · 2024Trial
- Sample enrichment for clinical trials to show delay of onset in huntington disease.Movement disorders : official journal of the Movement Disorder Society · 2019Trial
- Self-inactivating AAV-CRISPR at different ages enables sustained amelioration of Huntington's disease deficits in BAC226Q mice.Science advances · 2026Article
- Longitudinal analysis in Mecp2-het female mice reveals atypical nociceptive behaviours.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Unlocking the potential: advancements and applications of gene therapy in severe disorders.Annals of medicine · 2025Review
- Revolutionizing Huntington's Disease Treatment: Breakthroughs in AAV-Mediated Gene Therapy.Cells · 2025Review
- Emerging Trends and Hot Spots in Epigenetic Modifications in Neurology: A Bibliometric Analysis.Molecular neurobiology · 2025Review
- Epigenome Engineering Using dCas Systems for Biomedical Applications and Biotechnology: Current Achievements, Opportunities and Challenges.International journal of molecular sciences · 2025Review
- Advances in gene and cellular therapeutic approaches for Huntington's disease.Protein & cell · 2025Review
- Gene therapy for CNS disorders: modalities, delivery and translational challenges.Nature reviews. Neuroscience · 2024Review
- Epigenetic control of multiple genes with a lentiviral vector encoding transcriptional repressors fused to compact zinc finger arrays.Molecular therapy. Methods & clinical development · 2024Article
- Exploring molecular mechanisms, therapeutic strategies, and clinical manifestations of Huntington's disease.Archives of pharmacal research · 2024Review
- Systems for Targeted Silencing of Gene Expression and Their Application in Plants and Animals.International journal of molecular sciences · 2024Review
- Latest advances on new promising molecular-based therapeutic approaches for Huntington's disease.Journal of translational internal medicine · 2024Article
- Huntington's Disease: Complex Pathogenesis and Therapeutic Strategies.International journal of molecular sciences · 2024Review
- Nanoparticle-mediated delivery of non-viral gene editing technology to the brain.Progress in neurobiology · 2024Review
- Neurodegenerative Diseases: New Hopes and Perspectives.Current molecular medicine · 2024Review
- A Directed Evolution Protocol for Engineering Minimal Transcription Factors, Based on CIS Display.Methods in molecular biology (Clifton, N.J.) · 2024Article
38 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expanded CAG repeats in the huntingtin (HTT) gene. Although several palliative treatments are available, there is currently no cure and patients generally die 10-15 y after diagnosis. Several promising approaches for HD therapy are currently in development, including RNAi and antisense analogs. We developed a complementary strategy to test repression of mutant HTT with zinc finger proteins (ZFPs) in an HD model. We tested a "molecular tape measure" approach, using long artificial ZFP chains, designed to bind longer CAG repeats more strongly than shorter repeats. After optimization, stable ZFP expression in a model HD cell line reduced chromosomal expression of the mutant gene at both the protein and mRNA levels (95% and 78% reduction, respectively). This was achieved chromosomally in the context of endogenous mouse HTT genes, with variable CAG-repeat lengths. Shorter wild-type alleles, other genomic CAG-repeat genes, and neighboring genes were unaffected. In vivo, striatal adeno-associated virus viral delivery in R6/2 mice was efficient and revealed dose-dependent repression of mutant HTT in the brain (up to 60%). Furthermore, zinc finger repression was tested at several levels, resulting in protein aggregate reduction, reduced decline in rotarod performance, and alleviation of clasping in R6/2 mice, establishing a proof-of-principle for synthetic transcription factor repressors in the brain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.