ArticleNucleic acids research2017
Characterizing the effect of GalNAc and phosphorothioate backbone on binding of antisense oligonucleotides to the asialoglycoprotein receptor.
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 44 papers.
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Who cites it
44 citing papers in PubMed, 90 citations in OpenAlex.
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- Navigating the next frontier in biomedicine: breakthroughs and insights in nucleic acid therapeutics.Chemical science · 2026Review
- The efficacy of oligonucleotide-based gene therapeutics in gene silencing.Theranostics · 2026Review
- Ligand Valency and Linker Design Dictate the Efficacy of CI-M6PR-Mediated Targeted Delivery of M6P-siRNA Conjugates.ACS omega · 2025Article
- Modeling and Simulation Identifies Endocytosis Uptake Rate and Fraction Unbound as Important Predictors of Oligonucleotide Pharmacokinetics.CPT: pharmacometrics & systems pharmacology · 2025Article
- Zilebesiran as an Innovative siRNA-Based Therapeutic Approach for Hypertension: Emerging Perspectives in Cardiovascular Medicine.International journal of molecular sciences · 2025Review
- Innovative applications of silicon dioxide nanoparticles for targeted liver cancer treatment.Frontiers in bioengineering and biotechnology · 2025Review
- Glucose-induced LINC01419 reprograms the glycolytic pathway by recruiting YBX1 to enhance PDK1 mRNA stability in hepatocellular carcinoma.Clinical and translational medicine · 2024Article
- Nucleic acid drugs: recent progress and future perspectives.Signal transduction and targeted therapy · 2024Review
- Targeted Drug Delivery Strategies for the Treatment of Hepatocellular Carcinoma.Molecules (Basel, Switzerland) · 2024Review
- Enhancing the Effectiveness of Oligonucleotide Therapeutics Using Cell-Penetrating Peptide Conjugation, Chemical Modification, and Carrier-Based Delivery Strategies.Pharmaceutics · 2023Review
- Complex DNA Architectonics─Self-Assembly of Amphiphilic Oligonucleotides into Ribbons, Vesicles, and Asterosomes.Bioconjugate chemistry · 2023Article
- Chemistry of Therapeutic Oligonucleotides That Drives Interactions with Biomolecules.Pharmaceutics · 2022Review
- Beyond GalNAc! Drug delivery systems comprising complex oligosaccharides for targeted use of nucleic acid therapeutics.RSC advances · 2022Review
- Ligand conjugate SAR and enhanced delivery in NHP.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases.Pharmaceutics · 2021Article
- Review
- Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins.ACS central science · 2021Article
- Pharmacokinetics and Proceedings in Clinical Application of Nucleic Acid Therapeutics.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Review
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Targeted delivery of antisense oligonucleotides (ASO) to hepatocytes via the asialoglycoprotein receptor (ASGR) has improved the potency of ASO drugs ∼30-fold in the clinic (1). In order to fully characterize the effect of GalNAc valency, oligonucleotide length, flexibility and chemical composition on ASGR binding, we tested and validated a fluorescence polarization competition binding assay. The ASGR binding, and in vitro and in vivo activities of 1, 2 and 3 GalNAc conjugated single stranded and duplexed ASOs were studied. Two and three GalNAc conjugated single stranded ASOs bind the ASGR with the strongest affinity and display optimal in vitro and in vivo activities. 1 GalNAc conjugated ASOs showed 10-fold reduced ASGR binding affinity relative to three GalNAc ASOs but only 2-fold reduced activity in mice. An unexpected observation was that the ASGR also appears to play a role in the uptake of unconjugated phosphorothioate modified ASOs in the liver as evidenced by the loss of activity of GalNAc conjugated and unconjugated ASOs in ASGR knockout mice. Our results provide insights into how backbone charge and chemical composition assist in the binding and internalization of highly polar anionic single stranded oligonucleotides into cells and tissues.
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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.