ArticleMolecular therapy : the journal of the American Society of Gene Therapy2021
Ligand conjugate SAR and enhanced delivery in NHP.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 17 citations in OpenAlex.
- Skeletal muscle metabolism in health and disease: Mechanisms, interventions, and clinical perspectives.iScience · 2026Review
- Enhanced liver-targeted delivery with ribofuranose-based GalNAc conjugates.Molecular therapy. Nucleic acids · 2026Article
- Article
- Two Birds with One Stone: A Novel Dithiomaleimide-Based GalNAc-siRNA Conjugate Enabling Good siRNA Delivery and Traceability.Molecules (Basel, Switzerland) · 2023Article
- Multivalent Lactobionic Acid and N-Acetylgalactosamine-Conjugated Peptide Nucleic Acids for Efficient In Vivo Targeting of Hepatocytes.Advanced healthcare materials · 2023Article
- Combination treatment of mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Escaping to silence using an endosome-disrupting polymer.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
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14 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
N-Acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) are a leading RNA interference (RNAi) platform allowing targeted inhibition of disease-causing genes in hepatocytes. More than a decade of development has recently resulted in the first approvals for this class of drugs. While substantial effort has been made to improve nucleic acid modification patterns for better payload stability and efficacy, relatively little attention has been given to the GalNAc targeting ligand. In addition, the lack of an intrinsic endosomal release mechanism has limited potency. Here, we report a stepwise analysis of the structure activity relationships (SAR) of the components comprising these targeting ligands. We show that there is relatively little difference in biological performance between bi-, tri-, and tetravalent ligand structures while identifying other features that affect their biological activity more significantly. Further, we demonstrate that subcutaneous co-administration of a GalNAc-functionalized, pH responsive endosomal release agent markedly improved the activity and duration of effect for siRNA conjugates, without compromising tolerability, in non-human primates. These findings could address a significant bottleneck for future siRNA ligand conjugate development.
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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.