ArticleMolecular therapy. Nucleic acids2012
siRNA-optimized Modifications for Enhanced In Vivo Activity.
Article in Molecular therapy. Nucleic acids, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
What it found
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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.
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Who cites it
39 citing papers in PubMed.
- Chemical Modification Strategies for Therapeutic Oligonucleotides: Mechanism Compatibility, Design Trade-Offs, and Translational Barriers.Molecules (Basel, Switzerland) · 2026Review
- Working So Hard: Double-Stranded RNAs That Can Perform Both Gene Activation and Gene Silencing.Chembiochem : a European journal of chemical biology · 2026Article
- Evolution of siRNA Therapeutics: From Mechanistic Foundations to Clinical Expansion.Pharmaceutics · 2026Review
- An siRMSD parameter of structural distortion induced by chemical modification is predictive of the off-target effect of siRNA.Molecular therapy. Nucleic acids · 2025Article
- RNA chemistry and therapeutics.Nature reviews. Drug discovery · 2025Review
- Antisense molecules: A promising new therapy for atopic dermatitis.Acta pharmaceutica Sinica. B · 2025Review
- Discovery of long-acting APOC3 siRNA for treating patients with hypertriglyceridemia.Nucleic acids research · 2025Article
- Transient Knockdown of RORB with Cell-Penetrating siRNA Improves Visual Function in a Proteotoxic Mouse Model of Retinitis Pigmentosa.Biomedicines · 2025Article
- Improving the potency prediction for chemically modified siRNAs through insights from molecular modeling of individual sequence positions.Molecular therapy. Nucleic acids · 2025Article
- Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides.Molecules (Basel, Switzerland) · 2024Article
- Small interfering RNA (siRNA)-based therapeutic applications against viruses: principles, potential, and challenges.Journal of biomedical science · 2023Review
- Cytoplasmic delivery of siRNA using human-derived membrane penetration-enhancing peptide.Journal of nanobiotechnology · 2022Article
- Article
- Therapeutic siRNA: State-of-the-Art and Future Perspectives.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2022Review
- Inhaled siRNA Formulations for Respiratory Diseases: From Basic Research to Clinical Application.Pharmaceutics · 2022Review
- Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a).Nature medicine · 2022Article
- siRNAs containing 2'-fluorinated Northern-methanocarbacyclic (2'-F-NMC) nucleotides: in vitro and in vivo RNAi activity and inability of mitochondrial polymerases to incorporate 2'-F-NMC NTPs.Nucleic acids research · 2021Article
- Synthesis and evaluation of modified siRNA molecules containing a novel glucose derivative.RSC advances · 2021Article
- siRNA Therapeutics: Future Promise for Neurodegenerative Diseases.Current neuropharmacology · 2021Review
- Introducing an In Vitro Liver Stability Assay Capable of Predicting the In Vivo Pharmacodynamic Efficacy of siRNAs for IVIVC.Molecular therapy. Nucleic acids · 2020Article
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Current modifications used in small interfering RNAs (siRNAs), such as 2'-methoxy (2'-OMe) and 2'-fluoro (2'-F), improve stability, specificity or immunogenic properties but do not improve potency. These modifications were previously designed for use in antisense and not siRNA. We show, for the first time, that the siRNA-optimized novel 2'-O modifications, 2'-O-benzyl, and 2'-O-methyl-4-pyridine (2'-O-CH2Py(4)), are tolerated at multiple positions on the guide strand of siRNA sequences in vivo. 2'-O-benzyl and 2'-O-CH2Py(4) modifications were tested at each position individually along the guide strand in five sequences to determine positions that tolerated the modifications. The positions were combined together and found to increase potency and duration of siRNAs in vivo compared to their unmodified counterparts when delivered using lipid nanoparticles. For 2'-O-benzyl, four incorporations were tolerated with similar activity to the unmodified siRNA in vivo, while for 2'-O-CH2Py(4) six incorporations were tolerated. Increased in vivo activity was observed when the modifications were combined at positions 8 and 15 on the guide strand. Understanding the optimal placement of siRNA-optimized modifications needed for maximal in vivo activity is necessary for development of RNA-based therapeutics.
Identifiers
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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.