Programmable technologies to manipulate gene expression at the RNA level.

RNA has long been an enticing therapeutic target, but is now garnering increased attention, largely driven by clinical successes of RNA interference-based drugs. While gene knockdown by well-established RNA interference- and other oligonucleotide-based strategies continues to advance in the clinic, the repertoire of targetable effectors capable of altering gene expression at the RNA level is also rapidly expanding. In this review, we focus on several recently developed bifunctional molecular technologies that both interact with and act upon a target RNA. These new approaches for programmable RNA knockdown, editing, splicing, translation, and chemical modifications stand to provide impactful new modalities for therapeutic development in the coming decades.