The ‘dark transcriptome’ has been used to reduce inflammation in mice and human cells

Traditionally, the human genome has been considered a large instruction book for producing proteins. However, only a small portion of that “text” actually corresponds to coding instructions. Much of the rest is also transcribed into RNA, but without being translated into proteins. Among these molecules are the so-called long noncoding RNAs (lncRNAs): long RNA chains that, far from being genomic “noise,” perform essential regulatory functions, either by directly modulating gene expression or by acting indirectly on various cellular processes.

The article Human and mouse long noncoding RNAs reengineered for exogenous delivery reduce LPS-induced inflammation in human macrophages and mice illustrates well how this knowledge is beginning to have practical applications. The authors “copy” natural lncRNAs involved in inflammation, modify them to make them more stable and resistant to degradation, and encapsulate them in lipid nanoparticles, similar to those used in RNA vaccines. In doing so, they explore their therapeutic potential both in cellular models (human and murine macrophages treated with LPS) and in an animal model of LPS-induced inflammation. In both cases, administration of the modified lncRNAs reduced inflammatory markers.

This approach has several advantages. On the one hand, it starts from lncRNAs that are already present in the organism and whose physiological function is at least partially characterized, making it possible to rely on molecules “validated by biology” rather than on entirely synthetic designs. On the other hand, the strategy opens the door to a new category of RNA-based therapies that do not aim to replace proteins but rather to intervene directly in gene regulatory networks.

Nevertheless, the greatest challenge remains the effective delivery of nucleic acids. In this study, the choice of an “accessible” target such as the immune system—reachable through systemic administration—allows for a promising proof of principle. Extending this approach to other tissues—especially the central nervous system or skeletal muscle—poses much greater challenges, both because of the size and accessibility of these tissues and because of the need to cross complex biological barriers.

Overall, this is an inspiring piece of work that reflects the growing maturity of the field: we are moving from discovering what lncRNAs do to beginning to harness what they do. Much still needs to be optimized, but this is a clear sign that noncoding RNAs may come to occupy a place of their own within the therapeutic arsenal of the future.

The development of techniques for mass RNA sequencing (ribonucleic acid produced by transcription of DNA from our genome) is opening a field of scientific exploration of unexpected dimensions. We have already seen how messenger RNA–based vaccines have become part of everyday life, and small RNA molecules with low molecular weight are also being used in therapeutic treatments.

The study carried out in Canada by Janice Pang and colleagues and published in the scientific journal Science Signaling rigorously and pioneeringly describes the use of three long RNAs (lncRNAs) to control the inflammatory response in a model of induced inflammation in mice and in human macrophages. Considering that tens of thousands of these long RNAs still remain to be studied in order to understand their mechanisms of action, the possibility of their therapeutic use opens a very interesting field of research with multiple applications for the treatment of diseases for which we still do not have adequate drugs.

The press release is accurate and reflects well the work carried out and its potential therapeutic importance. It may be aimed at a more scientific audience and could be somewhat technical for a general readership.

There are many human diseases that are complex in terms of genetic and environmental factors—for example, the exaggerated response of the immune system in inflammatory processes or autoimmunity. Current treatments are usually generic immunosuppressive or immunomodulatory drugs, although the use of inhibitory treatments based on antibodies or recombinant proteins is increasingly widespread. In this article, the authors successfully explore extremely specific treatments at an earlier point in the flow of genetic information: instead of inhibiting the action of proteins such as cytokines, they prevent them from being produced by inhibiting the translation of messenger RNA. To do this, they genetically engineer little-known genetic elements, the so-called long noncoding RNAs (lncRNAs), directed against very specific cytokine RNAs, thereby reducing the inflammatory response both in human immune cells in vitro and in vivo in mice. In addition, they use liposomes as a method for delivering the RNA, avoiding unexpected responses that can occur when delivery is carried out using viral vectors.

I believe this is a highly precise biological therapeutic tool that has not yet been used and that offers many possibilities for treating diseases in which it is necessary to silence a gene or a particular signaling pathway—not only in immune diseases, but also in cancer or neurodegeneration.