Nobel Prize for the discovery of microRNA
Christian Bär on behalf of the ESC Working Group on Myocardial Function
The ESC Working Group on Myocardial Function warmly congratulates Victor Ambros and Gary Ruvkun, recipients of this year’s Nobel Prize in Physiology or Medicine, for their groundbreaking discovery of microRNA and its role in post-transcriptional gene regulation. Notably, this marks the second consecutive year the Nobel Prize has recognised pioneering work in the RNA field. Last year, Katalin Karikó and Drew Weissman were honoured for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19.
Both discoveries have revolutionised our understanding of the fine-tuning of gene regulation and opened new avenues of research. Most importantly, they have been instrumental in the shift from purely protein-centric approaches toward RNA-based therapies to treat and prevent human diseases.
The traditional view of gene expression is that the genetic information stored in our DNA is transcribed into RNAs that contain the messages (therefore called messenger RNA or mRNA) that are further translated into many thousands of specific proteins. While this still holds true, the process is far more intricate. Ambros and Ruvkun identified small RNA molecules that do not code for proteins but instead regulate protein production. These microRNAs bind to specific mRNAs and either block their translation into proteins or mark them for degradation. This regulatory role ensures that proteins are produced at the correct time and in the right quantities.
First discovered in the roundworm C. elegans, microRNAs are now known to be highly conserved across species, with at least 1,000 found in humans. Because one microRNAs can target multiple mRNAs, they can simultaneously influence a wide range of cellular processes, such as cell growth, division, and differentiation. Consequently, aberrant microRNA activity can disrupt normal gene expression patterns and been linked to numerous pathological conditions, including cancer, neurodegenerative disorders, and cardiovascular disease.
The rapid advancement in our understanding of microRNA mode of action has paved the way for the development of targeted disease treatments. In cases where microRNA levels are insufficient, synthetic microRNAs can be introduced to normalise them. Conversely, in instances where their expression is excessive, antisense-oligonucleotides (ASOs) can be employed to block them. This concept has been successfully validated in numerous preclinical studies over the past decades and is now entering clinical testing for the treatment of cardiovascular disease.
One notable advance comes from the lab of Prof. Thomas Thum, former Chairperson of the ESC Working Group on Myocardial Function. Over a decade ago, Prof. Thum's team discovered that the microRNA miR-132 drives pathological cardiac hypertrophy. In several small and large animal models of heart disease, they demonstrated that inhibiting miR-132 with a specific ASO could prevent cardiac remodeling and preserve heart function. These encouraging results led to the development of the miR-132 inhibitor CDR132L which has shown safety and tolerability in a Phase 1b clinical trial. Currently, CDR132L is undergoing evaluation in the Phase 2 HF-REVERT study, which involves 280 patients with reduced left ventricular ejection fraction following myocardial infarction. The first patient was enrolled in July 2022, and results are expected early next year.
In summary, the discovery of Ambros and Ruvkun has set the scene for RNA therapeutics, particularly those targeting microRNAs, which have significant potential for future cardiovascular therapies and beyond. Indeed, microRNA-based therapies are being explored in a variety of clinical settings. For instance, MRG-201, a synthetic miR-29 mimic, was trialled for the treatment of fibrotic skin conditions, while RG-012, an inhibitor of miR-21, was evaluated in a Phase 2 trial for the treatment of Alport syndrome, a genetic kidney disorder. These examples demonstrate the growing impact of RNA therapeutics across diverse medical fields, positioning microRNA modulation as a key player in the development of innovative treatments for previously challenging diseases.