Cardiac fibrosis describes the excessive proliferation of cardiac fibroblasts and extracellular matrix secretion leading to pathological stiffness and impaired function of the heart. Cardiac fibrosis is a hallmark of heart failure (HF) which is projected to remain the number one cause of death beyond 2030 and therefore represents a pressing social and economic burden worldwide. This implies the urgent need for therapeutics tackling cardiac fibrosis. However, specific treatments for cardiac fibrosis are lacking. RNAs that do not code for proteins comprise a large portion of the human genome. These so-called noncoding RNAs (ncRNAs) are emerging as important players in disease pathogenesis including cardiovascular disease, yet their functional roles are still ill understood. In this project we optimized a new ncRNA-based therapeutic approach targeting cardiac fibrosis specifically in human cells and thereby offering new options for treating patients suffering from HF. Specifically, we previously identified the long noncoding RNA (lncRNA) Meg3 as a novel and innovative target in HF pathologies with fibrosis in mice (Circ Res. 2017 Aug 18;121(5):575-583). This lncRNA was shown to regulate extracellular matrix remodeling through modulationof Matrix Metallopeptidase 2 (MMP2). Pharmacological inhibition of Meg3 prevented cardiac MMP2 induction, leading to reduced cardiac fibrosis and improved diastolic performance after pressure overload of the heart in mice. Here, we now optimized the chemical structure of the initial prototype inhibitor used in mouse for human applications. These new human based MEG3 inhibitors efficiently reduced the functional level of human MEG3 and its direct target MMP2 as well as of further fibrotic marker genes in both human cardiac fibroblasts in vitro and ex vivo in cultured living human myocardial tissue slices. The latter representing a highly innovative method that enables sophisticated translational and pre-clinical research and development. We further expanded the translational concept and applied the optimized human antiMEG3 inhibitor in pigs as a relevant large animal model. Strikingly, we have been able to demonstrate a reduction of functional Meg3 along with decreased MMP2 expression levels although the inhibitor was optimized for human and not for porcine Meg3.
Furthermore, we addressed additional key areas to advance our project from the commercial perspective. We have evaluated the current intellectual property position including a FTO analysis to pave the way for the future development of the candidate.
Together, these very encouraging early preclinical data and the favorable IP situation strongly warrant further development towards the clinic of our antiMEG3 inhibitor that indeed now was successful in an EIC Transition Open grant. Our vision is that this unique RNA-based approach will offer a new opportunity to revolutionize medical practice resulting into improved patient care in fibrotic subforms of heart failure.
