Investigating the pharmacodynamic durability of GalNAc-siRNA conjugates

Givosiran, a GalNAc-conjugated siRNA, which was recently approved on the market, displays sustained knock-down over month-long periods. The following paper investigates the reasons behind those impressive pharmacodynamic properties. After looking into various mechanisms related to stability, accumulation or entrapment, the authors conclude that the GalNAc-conjugated siRNAs can be retained in acidic intracellular compartments from where they get slowly released. Upon delivery to the cytosol, the drug can exhibit its therapeutic activity by loading into RISC. Results are also compared to LNPs loaded siRNAs. The increased half-life in these acidic organelles was revealed to account for most of the long-term activity of the therapeutic. The paper exposed a major factor of the mechanism of action of conjugated siRNAs.