ArticleNucleic acids research2026
Transient acute neuronal activation response caused by high concentrations of oligonucleotides in the cerebral spinal fluid.
Article in Nucleic acids research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy.Nature medicine · 2026Trial
- Addressing the needs of nano-rare patients: the n-Lorem experience.Nucleic acids research · 2026Review
- Guanine base modifications in antisense oligonucleotides mitigate acute central nervous system toxicity.RSC chemical biology · 2026Article
- Dolutegravir developmental toxicity is mitigated by magnesium and folate in zebrafish embryos.Disease models & mechanisms · 2026Article
- Divalent siRNA for prion disease.Nucleic acids research · 2026Article
- Divalent siRNA for prion disease.bioRxiv : the preprint server for biology · 2026Article
- Acute neuronal inhibition response caused by phosphorothioate antisense oligonucleotides following local delivery to the central nervous system.Nucleic acids research · 2026Article
- A splice-switching antisense oligonucleotide approach for pediatric genetic epilepsies.bioRxiv : the preprint server for biology · 2025Article
- Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid-siRNA conjugate administered into cerebrospinal fluid.Nucleic acids research · 2025Article
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Authors and funding
20 authors.
Funding
Abstract
Oligonucleotide (ON) therapeutics are promising as disease-modifying therapies for central nervous system (CNS) disorders. Intrathecal ON administration into the cerebral spinal fluid is a safe and effective delivery mode to the CNS. However, preclinical studies have shown acute and transient changes in neurobehavior following high-dose central ON delivery. Here, we characterize a subset of these changes peaking 15 min after ON dosing and resolving after 120 min. Symptoms include shaking, muscle twitching, cramping, hyperactivity, hyperreactivity, vocalizations, tremors, convulsions, and seizures. These are collectively referred to as the acute neuronal activation response. Acute neuronal activation is observed in rats, mice, and nonhuman primates and is quantifiable using a simple scoring system. It is distinct from acute inhibition seen with some phosphorothioate-modified antisense oligonucleotides, characterized by loss of spinal reflexes, ataxia, and sedation. The acute neuronal activation response is largely sequence-independent and is driven by ON chelation of divalent cations, particularly influenced by the divalent cation-to-ON ratio in the dosing solution. Acute neuronal activation can be safely mitigated by adjusting this ratio through magnesium supplementation in the ON formulation. We provide a comprehensive framework for quantifying and mitigating the acute neuronal activation response caused by high concentrations of centrally delivered ON therapeutics in preclinical species.
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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.