Novel Cluster and Monomer-Based GalNAc Structures Induce Effective Uptake of siRNAs in Vitro and in Vivo

Vivek K. Sharma, Maire F. Osborn, Matthew R. Hassler, Dimas Echeverria, Socheata Ly, Egor A. Ulashchik, Yury V. Martynenko-Makaev, Vadim V. Shmanai, Timofei S. Zatsepin, Anastasia Khvorova, Jonathan K. Watts

    Research output: Contribution to journalArticlepeer-review

    17 Citations (Scopus)

    Abstract

    GalNAc conjugation is emerging as a dominant strategy for delivery of therapeutic oligonucleotides to hepatocytes. The structure and valency of the GalNAc ligand contributes to the potency of the conjugates. Here we present a panel of multivalent GalNAc variants using two different synthetic strategies. Specifically, we present a novel conjugate based on a support-bound trivalent GalNAc cluster, and four others using a GalNAc phosphoramidite monomer that was readily assembled into tri- or tetravalent designs during solid phase oligonucleotide synthesis. We compared these compounds to a clinically used trivalent GalNAc cluster both in vitro and in vivo. In vitro, cluster-based and phosphoramidite-based scaffolds show a similar rate of internalization in primary hepatocytes, with membrane binding observed as early as 5 min. All tested compounds provided potent, dose-dependent silencing, with 2-4% of injected dose recoverable from liver after 1 week. The two preassembled trivalent GalNAc clusters showed higher tissue accumulation and gene silencing relative to di-, tri-, or tetravalent GalNAc conjugates assembled via phosphoramidite chemistry.

    Original languageEnglish
    Pages (from-to)2478-2488
    Number of pages11
    JournalBioconjugate Chemistry
    Volume29
    Issue number7
    DOIs
    Publication statusPublished - 18 Jul 2018

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