ArticleNucleic acids research2024
A programmable dual-targeting siRNA scaffold supports potent two-gene modulation in the central nervous system.
Article in Nucleic acids research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Albumin-binding dendrimer-conjugated siRNA enables safe and effective gene silencing throughout the central nervous system.Nucleic acids research · 2026Article
- The Biochemical and Genetic Architecture of Geographic Atrophy: The Role of the FHL-1/CFH Axis and the Paradigm of RNA Interference Therapeutics.Biomedicines · 2026Review
- Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality in an MECP2 duplication mouse model.Nature communications · 2026Article
- Precision RNAi for Fibrodysplasia Ossificans Progressiva: a combinatorial, unimolecular, allele selective approach.Research square · 2026Article
- Brain-targeted delivery of siRNA via non-viral delivery systems, the therapeutic strategy for Alzheimer's disease-Unveiling challenges and prospects.International journal of pharmaceutics: X · 2026Review
- Silencing Ubiquitin-Specific Peptidase 10 Alleviates Persistent Corneal Epithelial Defect in Mice.The American journal of pathology · 2026Article
- Transient acute neuronal activation response caused by high concentrations of oligonucleotides in the cerebral spinal fluid.Nucleic acids research · 2026Article
- mRNA-Encoded antibodies as a next-generation therapeutic paradigm: a rapid and adaptive platform for the prevention and treatment of emerging and re-emerging infectious diseases - A critical review.Immunologic research · 2026Review
- Huntington disease: somatic expansion, pathobiology and therapeutics.Nature reviews. Neurology · 2026Review
- Albumin-binding dendrimer-conjugated siRNA enables safe and effective gene silencing throughout the central nervous system.bioRxiv : the preprint server for biology · 2025Article
- SCAD: A modular platform for efficient delivery of duplex RNA to the CNS and beyond.Molecular therapy. Nucleic acids · 2025Article
- A novel bispecific siRNA concept: Efficient dual knockdown ofMolecular therapy. Nucleic acids · 2025Article
- Multi-Target Drug Design in Alzheimer's Disease Treatment: Emerging Technologies, Advantages, Challenges, and Limitations.Pharmacology research & perspectives · 2025Review
- Multimeric Conjugates Using Engineered Peptide Scaffolds for Efficient siRNA Delivery.Bioconjugate chemistry · 2025Article
- In Vitro Efficacy of PEI-Derived Lipopolymers in Silencing of Toxic Proteins in a Neuronal Model of Huntington's Disease.Pharmaceutics · 2025Article
- Modulation of TTR gene expression in the eye using modified siRNAs.Nucleic acids research · 2025Article
- Treatment of neurological pathology and inflammation in Machado-Joseph disease through in vivo self-assembled siRNA.Brain : a journal of neurology · 2025Article
- RNAi-based drug design: considerations and future directions.Nature reviews. Drug discovery · 2024Review
- Brain-Targeting siRNA Delivery to Tackle Alzheimer's Disease.Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnologyReview
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16 authors.
Funding
Abstract
Divalent short-interfering RNA (siRNA) holds promise as a therapeutic approach allowing for the sequence-specific modulation of a target gene within the central nervous system (CNS). However, an siRNA modality capable of simultaneously modulating gene pairs would be invaluable for treating complex neurodegenerative disorders, where more than one pathway contributes to pathogenesis. Currently, the parameters and scaffold considerations for multi-targeting nucleic acid modalities in the CNS are undefined. Here, we propose a framework for designing unimolecular 'dual-targeting' divalent siRNAs capable of co-silencing two genes in the CNS. We systematically adjusted the original CNS-active divalent siRNA and identified that connecting two sense strands 3' and 5' through an intra-strand linker enabled a functional dual-targeting scaffold, greatly simplifying the synthetic process. Our findings demonstrate that the dual-targeting siRNA supports at least two months of maximal distribution and target silencing in the mouse CNS. The dual-targeting divalent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g. Huntington's disease: MSH3 and HTT; Alzheimer's disease: APOE and JAK1) with similar potency to a mixture of single-targeting divalent siRNAs against each gene. This work enhances the potential for CNS modulation of disease-related gene pairs using a unimolecular siRNA.
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