Improved In Vivo Metabolic Stability and Silencing Efficacy of siRNAs with Phosphorothioate Linkage-Free, GalNAc-Conjugated Sense Strands Containing Morpholino-LNA Modifications

To ensure specificity, loading of the sense strand of small interfering RNAs (siRNAs) into RISC must be inhibited. We show here that siRNAs with 5′- and 6′-morpholino LNA residues or 6′-OH-LNA at the 5′ terminus of a fully phosphodiester sense strand resulted in metabolically stable siRNAs with a potency and a duration of action in mice that were greater than those of an siRNA in which the 5′ terminus of the sense strand has two terminal phosphorothioate linkages and regular LNA.