ArticleJCI insight2021
Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality in an MECP2 duplication mouse model.Nature communications · 2026Article
- Divalent siRNA for prion disease.Nucleic acids research · 2026Article
- Divalent siRNA for prion disease.bioRxiv : the preprint server for biology · 2026Article
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Comparison ofMolecular therapy. Nucleic acids · 2025Article
- RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.Molecular therapy : the journal of the American Society of Gene Therapy · 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
- Metabolic Stability and Targeted Delivery of Oligonucleotides: Advancing RNA Therapeutics Beyond The Liver.Journal of medicinal chemistry · 2025Review
- Chemical engineering of CRISPR-Cas systems for therapeutic application.Nature reviews. Drug discovery · 2025Review
- Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of CaMolecular therapy. Nucleic acids · 2024Article
- A minimally invasive endovascular approach to the cerebellopontine angle cistern enables broad CNS biodistribution of scAAV9-CB-GFP.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Identification of selective and non-selectiveMolecular therapy. Nucleic acids · 2024Article
- Lipid-siRNA conjugate accesses perivascular transport and achieves durable knockdown throughout the central nervous system.bioRxiv : the preprint server for biology · 2024Article
- A programmable dual-targeting siRNA scaffold supports potent two-gene modulation in the central nervous system.Nucleic acids research · 2024Article
- Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of CabioRxiv : the preprint server for biology · 2024Article
- A combinatorial approach for achieving CNS-selective RNAi.Nucleic acids research · 2024Article
- RNAi-based drug design: considerations and future directions.Nature reviews. Drug discovery · 2024Review
- Self-delivering, chemically modified CRISPR RNAs for AAV co-delivery and genome editing in vivo.Nucleic acids research · 2024Article
- MultiplexedNucleic acid therapeutics · 2024Article
- Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model.Molecular therapy. Methods & clinical development · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
Abstract
siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman primate brains upon direct cerebrospinal fluid (CSF) administration. Oligonucleotide distribution in the CNS is nonuniform, limiting clinical applications. The contribution of CSF infusion placement and dosing regimen on relative accumulation, specifically in the context of large animals, is not well characterized. To our knowledge, we report the first systemic, comparative study investigating the effects of 3 routes of administration - intrastriatal (i.s.), i.c.v., and intrathecal catheter to the cisterna magna (ITC) - and 2 dosing regimens - single and repetitive via an implanted reservoir device - on di-siRNA distribution and accumulation in the CNS of Dorset sheep. CSF injections (i.c.v. and ITC) resulted in similar distribution and accumulation across brain regions. Repeated dosing increased homogeneity, with greater relative deep brain accumulation. Conversely, i.s. administration supported region-specific delivery. These results suggest that dosing regimen, not CSF infusion placement, may equalize siRNA accumulation and efficacy throughout the brain. These findings inform the planning and execution of preclinical and clinical studies using siRNA therapeutics in the CNS.
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What OpenQuestion holds
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.