Editorial focus: understanding off-target effects as the key to successful RNAi therapy

Abstract

With the first RNA interference (RNAi) drug (ONPATTRO (patisiran)) on the market, we witness the RNAi therapy field reaching a critical turning point, when further improvements in drug candidate design and delivery pipelines should enable fast delivery of novel life changing treatments to patients. Nevertheless, ignoring parallel development of RNAi dedicated in vitro pharmacological profiling aiming to identify undesirable off-target activity may slow down or halt progress in the RNAi field. Since academic research is currently fueling the RNAi development pipeline with new therapeutic options, the objective of this article is to briefly summarize the basics of RNAi therapy, as well as to discuss how to translate basic research into better understanding of related drug candidate safety profiles early in the process.

Keywords: Off-target effects; RNAi drug candidates; RNAi therapy; microRNAs; ncRNAs; siRNAs.

Fig. 1.

Schematic representation of the RNAi drug discovery and development process. Full mechanistic understanding of the disease allows selection of highly disease specific therapy targets, and thus early elimination of off-targets. In the first phase, candidate sequence design and optimization allows early hazard identification and elimination, whereas chemical modifications can be applied to design out potential hazards and limitations. Furthermore, in later phases potential liabilities regarding delivery system choice should be assessed. Finally, broad pharmacological profiles of the lead drug candidates should be obtained, before drug candidates undergo further clinical development