ArticleNucleic acids research2019
Safety evaluation of 2'-deoxy-2'-fluoro nucleotides in GalNAc-siRNA conjugates.
Article in Nucleic acids research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Considerations and recommendations for assessment of plasma protein binding and drug-drug interactions for siRNA therapeutics.Nucleic acids research · 2022Pooled it
- Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data.ESC heart failure · 2021Trial
- Small Nucleic Acid Therapeutics for Ocular Diseases: Progress, Challenges, and Future Perspectives.Pharmaceutics · 2026Review
- Discovery of long-acting APOC3 siRNA for treating patients with hypertriglyceridemia.Nucleic acids research · 2025Article
- Stereo-random oligonucleotides enable efficient recruitment of ADAR in vitro and in vivo.Nature communications · 2025Article
- Translational and clinical development of therapeutic siRNA and ASOs: current industry practices, perspectives, and recommendations.Nucleic acids research · 2025Article
- siRNA Therapeutics for the Treatment of Hereditary Diseases and Other Conditions: A Review.International journal of molecular sciences · 2025Review
- Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines.Signal transduction and targeted therapy · 2025Review
- Nucleic acid drugs: recent progress and future perspectives.Signal transduction and targeted therapy · 2024Review
- The Impact of Chemical Modifications on the Interferon-Inducing and Antiproliferative Activity of Short Double-Stranded Immunostimulating RNA.Molecules (Basel, Switzerland) · 2024Article
- Counteracting Angiotensinogen Small-Interfering RNA-Mediated Antihypertensive Effects With REVERSIR.Hypertension (Dallas, Tex. : 1979) · 2024Article
- Frameworks for transformational breakthroughs in RNA-based medicines.Nature reviews. Drug discovery · 2024Review
- RNAi-based drug design: considerations and future directions.Nature reviews. Drug discovery · 2024Review
- LDLR-Mediated Targeting and Productive Uptake of siRNA-Peptide Ligand Conjugates In Vitro and In Vivo.Pharmaceutics · 2024Article
- Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors.Molecular therapy. Nucleic acids · 2024Article
- RNA interference in the era of nucleic acid therapeutics.Nature biotechnology · 2024Review
- Chemistry, structure and function of approved oligonucleotide therapeutics.Nucleic acids research · 2023Review
- Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes.British journal of pharmacology · 2023Article
- Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates.Nature biotechnology · 2022Article
- Preclinical Toxicological Assessment of A Novel siRNA, SLN360, Targeting Elevated Lipoprotein (a) in Cardiovascular Disease.Toxicological sciences : an official journal of the Society of Toxicology · 2022Article
Corrections and comments
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Authors and funding
34 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
For oligonucleotide therapeutics, chemical modifications of the sugar-phosphate backbone are frequently used to confer drug-like properties. Because 2'-deoxy-2'-fluoro (2'-F) nucleotides are not known to occur naturally, their safety profile was assessed when used in revusiran and ALN-TTRSC02, two short interfering RNAs (siRNAs), of the same sequence but different chemical modification pattern and metabolic stability, conjugated to an N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Exposure to 2'-F-monomer metabolites was low and transient in rats and humans. In vitro, 2'-F-nucleoside 5'-triphosphates were neither inhibitors nor preferred substrates for human polymerases, and no obligate or non-obligate chain termination was observed. Modest effects on cell viability and mitochondrial DNA were observed in vitro in a subset of cell types at high concentrations of 2'-F-nucleosides, typically not attained in vivo. No apparent functional impact on mitochondria and no significant accumulation of 2'-F-monomers were observed after weekly administration of two GalNAc-siRNA conjugates in rats for ∼2 years. Taken together, the results support the conclusion that 2'-F nucleotides can be safely applied for the design of metabolically stabilized therapeutic GalNAc-siRNAs with favorable potency and prolonged duration of activity allowing for low dose and infrequent dosing.
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