Improved <i>In Vivo</i> 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.
Authors
- June Qin
- Daniel P. Donnelly (ORCID: https://orcid.org/0000-0002-7846-322X)
- Dhrubajyoti Datta (ORCID: https://orcid.org/0000-0003-2077-1294)
- Sally Schofield
- Ju Liu (ORCID: https://orcid.org/0000-0003-1030-9266)
- Jason A. Gilbert (ORCID: https://orcid.org/0000-0002-3182-7014)
- Rohan Degaonkar
- Muthiah A. Manoharan (ORCID: https://orcid.org/0000-0002-7931-1172)
- Martin Egli (ORCID: https://orcid.org/0000-0003-4145-356X)
- Pawan Kumar (ORCID: https://orcid.org/0000-0001-7936-4613)
- Jayanta Kundu (ORCID: https://orcid.org/0000-0003-2669-8112)
Institutions
- Alnylam Pharmaceuticals (United States) (US)
- Vanderbilt University (US)
Publication Details
- Journal
- Organic Letters
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1021/acs.orglett.4c02903
- Citations
- 8
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 1.87