ArticleNature communications2025
The nucleobase guanine at the 3'-terminus of oligonucleotide RGLS4326 drives off-target AMPAR inhibition and CNS toxicity.
Article in Nature communications, 2025. 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.
- RNA therapeutics: current status and future directions.Signal transduction and targeted therapy · 2026Review
- Pre-activation and gating pathway of AMPA receptors revealed by full and partial agonists.Nature structural & molecular biology · 2026Article
- SafeSense: An open-access safety atlas for antisense oligonucleotides adverse events in human.Molecular therapy. Nucleic acids · 2026Article
- Design of Nanocarriers for Kidney Targeted Delivery of Nucleic Acid Therapeutics.Macromolecular bioscience · 2026Review
- Disruption of a six-nucleotide miRNA motif improves PKD1 dosage and ameliorates polycystic kidney disease.Nucleic acids research · 2026Article
- MicroRNAs and immunotherapy in testicular germ cell tumors: opportunities and challenges for modulation of the immune microenvironment.Frontiers in immunology · 2026Review
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Authors and funding
22 authors.
Funding
Abstract
Designing safe and effective oligonucleotide (ON) therapeutics requires thorough understanding of structural-activity relationship (SAR) with the intended on-target(s) as well as the unintended off-target(s). Despite encouraging pharmacodynamic activity in a Phase 1b study, development of the first-generation anti-miR-17 ON RGLS4326 for the treatment of autosomal dominant polycystic kidney disease was discontinued due to dose-limiting central nervous system (CNS)-related toxicity observed in nonclinical chronic toxicity studies. Here, we provide SAR evidence that the nucleobase guanine at the 3'-terminus of RGLS4326 drives an unexpected off-target aptamer-like direct interaction with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), thereby causing CNS toxicity. By replacing the 3'-terminal guanine with adenine, we discover the next-generation anti-miR-17 RGLS8429 that is devoid of off-target AMPAR interaction and CNS toxicity while preserving the potency against the on-target miR-17. Here, we show a way to avoid off-target CNS effects and, more importantly, data that support the clinical development of RGLS8429.
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Registered trials
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