ArticleNucleic acids research2017
Phosphorylation-specific status of RNAi triggers in pharmacokinetic and biodistribution analyses.
Article in Nucleic acids research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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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
12 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Model-based meta-analysis to quantify the effects of short interfering RNA therapeutics on hepatitis B surface antigen turnover in hepatitis B-infected mice.CPT: pharmacometrics & systems pharmacology · 2024Pooled it
- RNA Therapeutics in Viral Infections and Cancer: Mechanisms, Challenges, and Prospects: A Review.Pharmaceutics · 2026Review
- Article
- Hepatitis B Core-Related Antigen and New Therapies for Hepatitis B.Microorganisms · 2021Review
- Pharmacodynamic and Pharmacokinetic Properties of Full Phosphorothioate Small Interfering RNAs for Gene SilencingNucleic acid therapeutics · 2021Article
- Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection.Scientific reports · 2021Article
- Article
- The Role of Hepatitis B Core-Related Antigen.Genes · 2019Review
- Application of Locked Nucleic Acid Oligonucleotides for siRNA Preclinical Bioanalytics.Scientific reports · 2019Article
- Review
- Pharmacokinetic Profiling of Conjugated Therapeutic Oligonucleotides: A High-Throughput Method Based Upon Serial Blood Microsampling Coupled to Peptide Nucleic Acid Hybridization Assay.Nucleic acid therapeutics · 2017Article
- 5΄-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo.Nucleic acids research · 2017Article
Corrections and comments
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The RNA interference (RNAi)-based therapeutic ARC-520 for chronic hepatitis B virus (HBV) infection consists of a melittin-derived peptide conjugated to N-acetylgalactosamine for hepatocyte targeting and endosomal escape, and cholesterol-conjugated RNAi triggers, which together result in HBV gene silencing. To characterize the kinetics of RNAi trigger delivery and 5΄-phosphorylation of guide strands correlating with gene knockdown, we employed a peptide-nucleic acid (PNA) hybridization assay. A fluorescent sense strand PNA probe binding to RNAi duplex guide strands was coupled with anion exchange high performance liquid chromatography to quantitate guide strands and metabolites. Compared to PCR- or ELISA-based methods, this assay enables separate quantitation of non-phosphorylated full-length guide strands from 5΄-phosphorylated forms that may associate with RNA-induced silencing complexes (RISC). Biodistribution studies in mice indicated that ARC-520 guide strands predominantly accumulated in liver. 5΄-phosphorylation of guide strands was observed within 5 min after ARC-520 injection, and was detected for at least 4 weeks corresponding to the duration of HBV mRNA silencing. Guide strands detected in RISC by AGO2 immuno-isolation represented 16% of total 5΄-phosphorylated guide strands in liver, correlating with a 2.7 log10 reduction of HBsAg. The PNA method enables pharmacokinetic analysis of RNAi triggers, elucidates potential metabolic processing events and defines pharmacokinetic-pharmacodynamic relationships.
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