ArticleNature communications2026
Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality in an MECP2 duplication mouse model.
Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Albumin-binding dendrimer-conjugated siRNA enables safe and effective gene silencing throughout the central nervous system.Nucleic acids research · 2026Article
- Organyl 5'-Phosphates in siRNA Guide Strands: Structure-Function Relationships Governing Anchoring in Argonaute 2 and Metabolic Stability.bioRxiv : the preprint server for biology · 2026Article
- Silencing Ubiquitin-Specific Peptidase 10 Alleviates Persistent Corneal Epithelial Defect in Mice.The American journal of pathology · 2026Article
- Albumin-binding dendrimer-conjugated siRNA enables safe and effective gene silencing throughout the central nervous system.bioRxiv : the preprint server for biology · 2025Article
- Potent and durable gene modulation in heart and muscle with chemically defined lipophilic siRNAs.Nucleic acids research · 2025Article
- Immunomodulation of behavior impairment via spleen-specific targeting lipid nanoparticles in a MeCP2 transgenic mouse model.Scientific reports · 2025Article
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Abstract
MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing therapies for MDS is challenging due to the variability in MECP2 expression among patients and the risk of inducing Rett syndrome through excessive pharmacological intervention. Reducing dosage to optimize silencing often compromises durability and necessitates increased dosing frequency. We present here a series of fully chemically modified small interfering RNAs (siRNAs) designed for isoform-selective and total Mecp2 silencing. Among these, we identify six lead siRNA candidates across two chemical scaffolds, achieving targeted total Mecp2 expression reductions ranging from 25% to 75%, sustained for at least four months following a single administration. The efficacy and safety of human ortholog silencing are evaluated using a mouse model with ~8-fold human Mecp2 transgene expression. In this severe duplication model, a single dose of the total isoform-silencing siRNA rescues early mortality and select behavioral impairments. Overall, this study introduces preclinical candidates for the treatment of MDS. Furthermore, it establishes a target selection strategy applicable to other dosage-sensitive gene imbalances.
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