Heart failure (HF) is a progressive and chronic inability of the heart to provide sufficient blood and oxygen to the organs. HF represents the most common cause of morbidity and mortality with pressing social and economic burden worldwide.
A main driver of HF development and progression is cardiac fibrosis, which describes the excessive deposition of extracellular matrix (ECM) proteins leading to continuous scarring and stiffening of the heart muscle. This impedes efficient re-filling of the left ventricle with blood during diastole leading to diastolic dysfunction and an impaired cardiac function. Initially, fibrosis is a reparative mechanism as it is part of tissue repair processes during wound healing. At present, HF remains a deadly disease with limited therapeutic options to treat cardiac fibrosis, which underlines the need for innovative therapies.
Over the last decades, noncoding RNAs (ncRNAs) have emerged as promising therapeutic targets. These RNAs, in contrast to the well-known messenger RNA (mRNA), do not encode proteins but constitute the vast majority of the transcriptome. Recent updates of the human genome project, it was revealed that in fact only 2-3 % of all gene transcripts are protein-coding. This strongly emphasizes the importance of ncRNAs, which were dramatically underestimated before. However, they have emerged as crucial regulators orchestrating diverse physiological and pathological mechanisms impinging on virtually all levels of gene expression in health and disease. The group of ncRNAs is quite diverse including e.g. microRNA (miRNAs), circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) which are defined by their size, structure and function.
NcRNAs are involved in the regulation and development of various illnesses including cardiovascular diseases. Their often context-specific expression makes them interesting therapeutic targets, which can be modulated in order to induce beneficial effects on pathological processes. In fact, first medications based on miRNAs have already entered clinical testing. However, compared to miRNAs, lncRNAs are so far less investigated, mainly due to their later discovery and functional complexity, explaining why up to now no clinical trials targeting lncRNAs have been performed. Nevertheless, promising pre-clinical data identified specific lncRNAs involved in the regulation of for example cardiac muscle growth referred to as cardiac hypertrophy (Han et al., 2014; Viereck et al., 2016; Piccoli et al., 2017; Viereck et al., 2020). However, favourable lncRNA-based targets to directly tackle cardiac fibrosis are scarce. Interestingly, in previous work, Prof. Thum and colleagues (Institute of Molecular and Translational Therapeutic Strategies (IMTTS)) could identify the lncRNA Meg3 as an encouraging target regarding the treatment of HF-associated fibrosis (Piccoli et al., 2017). Its critical role in the development of cardiac fibrosis could be validated in vitro by treating human cardiac fibroblasts with a Meg3 inhibitor, which induces an anti-fibrotic response. Meg3 inhibition was even able to reduce cardiac fibrosis in a mouse model of HF and to improve the diastolic function. Mechanistically, Meg3 is known to regulate matrix metalloproteinases in the heart. These enzymes are able to degrade extracellular matrix proteins and are therefore important for fibrotic processes. Meg3 is very well conserved among different species including human, which is rather uncommon for lncRNAs suggesting a higher translatability of the results to the human context.
Based on these promising results the project FIBREX („Targeting cardiac fibrosis with next generation RNA therapeutics”) was initiated aiming at further developing the anti-Meg3 therapeutic strategy. Within this project, an antisense oligonucleotide (ASO) specifically inhibiting Meg3 is applied. ASOs are chemically engineered single-stranded oligonucleotides (DNA/RNA molecules) designed to inhibit targeted RNA transcripts by inducing their degradation. Within FIBREX a novel Meg3-specific ASO-based therapeutic for the treatment of HF derived from cardiac fibrosis will be established. By completing non-clinical pharmacokinetics and safety studies in rats and minipigs as well as pharmacodynamics studies in a large animal model of HF the anti-Meg3 inhibitor will be developed close to clinical readiness. For this purpose, the IMTTS received a funding of 2.5 million Euro by the European Innovation Council (EIC). The development of a unique ASO-based anti-Meg3 therapy for HF derived from excessive fibrosis offers a new opportunity to revolutionize medical practice, reduce health costs and improve patient’s life.
