ArticleNucleic acids research2013
Rational design of antisense oligonucleotides targeting single nucleotide polymorphisms for potent and allele selective suppression of mutant Huntingtin in the CNS.
Article in Nucleic acids research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 158 citations in OpenAlex.
- SafeSense: An open-access safety atlas for antisense oligonucleotides adverse events in human.Molecular therapy. Nucleic acids · 2026Article
- Chemical Modification Strategies for Therapeutic Oligonucleotides: Mechanism Compatibility, Design Trade-Offs, and Translational Barriers.Molecules (Basel, Switzerland) · 2026Review
- ClinASO: An open-source platform for rapid drug discovery of gapmer antisense oligonucleotides.Molecular therapy. Nucleic acids · 2026Article
- Gene therapy for huntington's disease: advances, challenges, and future perspectives.Neurogenetics · 2026Review
- Model selection in preclinical nucleic acid therapeutics research.Communications biology · 2026Review
- Antisense oligonucleotides to KIF1A polymorphisms expand targets and rescue patient-derived neurons in vitro.Nature communications · 2026Article
- Development of Antisense Gapmers for the Treatment of Huntington's Disease.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Antisense oligonucleotide therapy mitigates autosomal dominant progressive hearing loss in a murine model of human DFNA2.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder.Molecular therapy. Nucleic acids · 2025Article
- Design and Preliminary Screen of Antisense Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Quantifying and mitigating motor phenotypes induced by antisense oligonucleotides in the central nervous system.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Therapeutic targeting of RNA for neurological and neuromuscular disease.Genes & development · 2024Review
- Strategies to improve the design of gapmer antisense oligonucleotide on allele-specific silencing.Molecular therapy. Nucleic acids · 2024Article
- Development of super-specific epigenome editing by targeted allele-specific DNA methylation.Epigenetics & chromatin · 2023Article
- Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking.Cells · 2023Review
- Rhodopsin-associated retinal dystrophy: Disease mechanisms and therapeutic strategies.Frontiers in neuroscience · 2023Review
- Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases.Pharmaceutics · 2022Review
- Identification of nucleobase chemical modifications that reduce the hepatotoxicity of gapmer antisense oligonucleotides.Nucleic acids research · 2022Article
- Haplotype-specific insertion-deletion variations for allele-specific targeting in Huntington's disease.Molecular therapy. Methods & clinical development · 2022Article
- Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1.The Journal of clinical investigation · 2022Article
29 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Autosomal dominant diseases such as Huntington's disease (HD) are caused by a gain of function mutant protein and/or RNA. An ideal treatment for these diseases is to selectively suppress expression of the mutant allele while preserving expression of the wild-type variant. RNase H active antisense oligonucleotides (ASOs) or small interfering RNAs can achieve allele selective suppression of gene expression by targeting single nucleotide polymorphisms (SNPs) associated with the repeat expansion. ASOs have been previously shown to discriminate single nucleotide changes in targeted RNAs with ∼5-fold selectivity. Based on RNase H enzymology, we enhanced single nucleotide discrimination by positional incorporation of chemical modifications within the oligonucleotide to limit RNase H cleavage of the non-targeted transcript. The resulting oligonucleotides demonstrate >100-fold discrimination for a single nucleotide change at an SNP site in the disease causing huntingtin mRNA, in patient cells and in a completely humanized mouse model of HD. The modified ASOs were also well tolerated after injection into the central nervous system of wild-type animals, suggesting that their tolerability profile is suitable for advancement as potential allele-selective HD therapeutics. Our findings lay the foundation for efficient allele-selective downregulation of gene expression using ASOs-an outcome with broad application to HD and other dominant genetic disorders.
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