While efficacious in many contexts, this paradigm had not been easily applied to the multitude of diseases that are caused by insufficient expression of biologically vital proteins. In general, it has been easier to find such molecules with inhibitory or antagonistic effects 1. Traditionally, therapeutic development involved the discovery of protein-targeting small molecules. This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic. Such approaches can directly target the stability of mRNAs or modulate non-coding RNA-mediated regulation of transcription and translation. In addition to RNA-targeting small molecules, new nucleic acid-based therapeutic modalities that allow highly specific modulation of RNA-based regulatory networks are being developed.

Recent discoveries of the extensive regulatory networks formed by non-coding RNAs offer alternative targets and strategies to amplify the production of a specific protein. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein.

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