The design, pharmacology, and toxicology exploring of a novel chemically modified siRNA targeting hepatic angiotensinogen with potential application for hypertension treatment
Angiotensinogen is the precursor of angiotensin II, a potent vasopressor in the renin-angiotensin-aldosterone system. Small interfering RNAs targeting hepatic angiotensinogen have been proven to be effective on blood pressure lowering in hypertension patients through reducing AGT levels in blood, and such effect could last over 6 months. Existing siRNA molecules has been high effective. However, it may be possible to develop novel siRNA molecules with improved inhibitory activity and longer duration period. In this study, we demonstrated an entire development process for a novel siRNA targeting hepatic angiotensinogen. Through proper combination of bioinformatics on-target/off-target screening on sequences, chemical modification patterns and liver-targeting delivery ligands, we have developed siRNA molecules with equivalent or better inhibitory activity, duration of effect and safety profile compared with siRNA molecules discovered previously. Furthermore, our analysis also revealed the correlation between efficacy and free energy of siRNAs. At present, no model can accurately predict the activity and off-target risk of fully modified siRNA molecules, thus efficient screening procedures are essential during the development of siRNA candidates. This study has provided a detailed and useful reference for the development of potent and safe siRNAs, which could also guide the future development of siRNAs on other targets. Overall design: RNAseq of primary rat or human hepatocytes treated with 1 nM, 10 nM or 100 nM of different siRNAs