Long non-coding RNA-targeting therapeutics: discovery and development update.

INTRODUCTION: lncRNAs are major players in regulatory networks orchestrating multiple cellular functions, such as 3D chromosomal interactions, epigenetic modifications, gene expression and others. Due to progress in the development of nucleic acid-based therapeutics, lncRNAs potentially represent easily accessible therapeutic targets. AREAS COVERED: Currently, significant efforts are directed at studies that can tap the enormous therapeutic potential of lncRNAs. This review describes recent developments in this field, particularly focusing on clinical applications. EXPERT OPINION: Extensive druggable target range of lncRNA combined with high specificity and accelerated development process of nucleic acid-based therapeutics open new prospects for treatment in areas of extreme unmet medical need, such as genetic diseases, aggressive cancers, protein deficiencies, and subsets of common diseases caused by known mutations. Although currently wide acceptance of lncRNA-targeting nucleic acid-based therapeutics is impeded by the need for parenteral or direct-to-CNS administration, development of less invasive techniques and orally available/BBB-penetrant nucleic acid-based therapeutics is showing early successes. Recently, mRNA-based COVID-19 vaccines have demonstrated clinical safety of all aspects of nucleic acid-based therapeutic technology, including multiple chemical modifications of nucleic acids and nanoparticle delivery. These trends position lncRNA-targeting drugs as significant players in the future of drug development, especially in the area of personalized medicine.

Amplifying gene expression with RNA-targeted therapeutics.

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.

Natural antisense transcripts as drug targets.

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.

A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease.

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.

Developing a new drug that is both safe and effective is a complex and expensive endeavor. An alternative approach is to 'repurpose' existing, safe compounds ­ that is, to establish if they could treat conditions others than the ones they were initially designed for. To achieve this, methods that can predict the activity of thousands of established drugs are necessary. These approaches are particularly important for conditions for which it is hard to find promising treatment. This includes, for instance, heart failure, dementia and other diseases that are linked to the activity of the hormone insulin becoming modified throughout the body, a defect called insulin resistance. Unfortunately, it is difficult to model the complex actions of insulin using cells in the lab, because they involve intricate networks of proteins, tissues and metabolites. Timmons et al. set out to develop a way to better assess whether a drug could be repurposed to treat insulin resistance. The aim was to build a biological signature of the disease in multiple human tissues, as this would help to make the findings more relevant to the clinic. This involved examining which genes were switched on or off in thousands of tissue samples from patients with different degrees of insulin resistance. Importantly, some of the patients had their condition reversed through lifestyle changes, while others did not respond well to treatment. These 'non-responders' provided crucial new clues to screen for active drugs. Carefully piecing the data together revealed the molecules and pathways most related to the severity of insulin resistance. Cross-referencing these results with the way existing drugs act on gene activity, highlighted 138 compounds that directly bind 73 proteins responsible for regulating insulin resistance pathways. Some of the drugs identified are suitable for short-term clinical studies, and it may even be possible to rank similar compounds based on their chemical activity. Beyond giving a glimpse into the complex molecular mechanisms of insulin resistance in humans, Timmons et al. provide a fresh approach to how drugs could be repurposed, which could be adapted to other conditions.