Publication - Abstract
Jun 15, 2018
Molecular therapy
August 18, 2020
In this paper Alnylam Pharmaceuticals, developer of RNAi therapeutics ONPATTRO® and GIVLAARI®, investigated the extended duration of N-acetylgalactosamine silencing RNA (GalNAc-siRNA) activity observed in vivo. Using the advanced Enhanced Stabilization Chemistry (ESC) design of GalNAc-siRNA, they performed in vitro studies with naked GalNAc-siRNAs and in vivo rodent studies with naked GalNAc-siRNAs and GalNAc-siRNAs in lipid nanoparticles (LNP).
They found that "acidic intracellular compartments are long-term depot" for GalNAc–siRNA conjugates and are responsible for the long-lasting activity observed in vivo, effectively precluding subcutaneous site of injection as a depot for siRNA. In addition, the mode of GalNAc-siRNAs delivery was found to have a significant impact on siRNA efficacy and duration, with LNP delivery requiring a lower dose to achieve a similar knockdown effect as naked GalNAc-siRNAs. The LNPs used in this study were prepared using NanoAssemblr technology and had a mean diameter of ∼65 nm with excellent homogeneity (PDI = 0.05).
These findings demonstrate that an improved siRNA LNP drug design can minimize degradation, amplifying target knockdown and duration of effect.
Publication - Abstract
Jun 15, 2018
Molecular therapy
Publication - Abstract
Jun 03, 2017
Molecular Pharmaceutics
Small interfering RNAs (siRNA) have a broad potential as therapeutic agents to reversibly silence any target gene of interest. The clinical application of siRNA requires the use of safe and effective delivery systems. In this study, we investigated...