Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations. 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. 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. Such approaches can directly target the stability of mRNAs or modulate non-coding RNA-mediated regulation of transcription and translation. This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic.

The recent discovery of vast non-coding RNA-based regulatory networks that can be easily modulated by nucleic acid-based drugs has opened numerous new therapeutic possibilities. Long non-coding RNA, and natural antisense transcripts (NATs) in particular, play a significant role in networks that involve a wide variety of disease-relevant biological mechanisms such as transcription, splicing, translation, mRNA degradation and others. Currently, significant efforts are dedicated to harnessing these newly emerging NAT-mediated biological mechanisms for therapeutic purposes. This review will highlight the recent clinical and pre-clinical developments in this field and survey the advances in nucleic acid-based drug technologies that make these developments possible.

Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.

E arly in my career, I learned a key lesson in communication in a one-to-one conversation with a senior executive at Coca-Cola. I was trying to convince him to focus more energy on improving the quality of the financial controls inside one international business division. Initially, I centered my conversation on the problem-the breakdowns in controls and the lack of quality financial information coming from his operation. The executive got angry, and I realized I had offended him. The rest of our conversation was unproductive.I decided to pull back. About a week later, after speaking to this executive's coworkers, I decided to take another approach. This time, I began our discussion by pointing out how he had succeeded with his division because he was an effective decision maker. I emphasized that I recognized that his influence had dramatically strengthened the operations for which he was responsible. After I recognized his importance to the company and his value as an individual, he relaxed.Then I pointed out that perhaps we could improve the amount of information that he had available to him about his organization's operational performance. He seemed interested. Therefore, I suggested that having more information-the kind that required stronger information and control systems-would help him make even better and faster decisions. By then he was paying close attention, even nodding in agreement. He understood that improving these systems would be win-win for the company and for him.By working to connect with him-and by understanding and acknowledging his skills and strengths as a leader-I was able to offer a scenario that appealed to him and that he would support.

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