Project description
Targeting non-coding circular RNAs in heart failure therapy
The major causes of heart failure are cardiac remodelling processes at the molecular, cellular and tissue level. The EU-funded REVERSE project will investigate the involvement of the non-coding circular RNA (circRNA) in cardiac injury associated with chemotherapy-induced cardiotoxicity and SARS CoV 2 infection. Multiple molecular circRNA signatures were discovered during the remodelling of cardiac cells and tissues in mice models and humans. The non-coding circRNAs are stable and species-conserved, representing ideal drug targets. The project aims to identify key circRNAs involved in remodelling processes using functional CRISPR-Cas library screening and validation in the human myocardial tissue model. The selected candidates will be tested in both chemotherapy-induced cardiotoxicity and SARS CoV-2-induced cardiac disease models.
Objective
Heart failure (HF) is a most common cause of mortality with currently >60 million of affected patients. Numbers will increase due to socioeconomic factors and as a result of the current COVID-19 pandemic. A major underlying cause of HF are cardiac remodelling processes at the molecular, cellular and tissue level. We will here focus on noncoding circular RNAs (circRNA) involved in two distinct forms of cardiac injury, chemotherapy-induced cardiotoxicity and SARS-CoV-2-infection, where currently no specific treatment strategies are available to reverse disease pathology. First proof-of-concept studies targeting the cardiac remodelling process by noncoding RNA modulation have been pioneered by us and were recently tested in a world-wide first clinical phase 1b study in HF patients. Within the family of non-coding RNAs, circRNAs are stable and species-conserved and thus ideal drug targets. We discovered multiple molecular circRNA signatures during remodelling of cardiac cells and tissues from mice and patients. We now aim to lift our research to its next inflection point with the following steps and interconnected objectives: a) discover key functional circular RNAs involved in remodelling processes by functional CRISPR-Cas library screening; b) validate circRNAs by manipulating human living beating myocardial tissue, c) explore their mode of action; and d) perform targeted cardiac delivery approaches of selected candidates in both chemotherapy-induced cardiotoxicity and SARS-CoV-2-induced cardiac disease models. A combination of bioinformatic, molecular and physiology-based methods, unique established noncoding RNA drug discovery pipelines, availability of modern S3-safety labs, large clinical biobanks and (fresh) human cardiac tissue for slicing preparations form the basis for a successful strategy. REVERSE aims to discover fundamentally new therapeutic entry points for two forms of cardiac injuries, where currently no disease-specific treatments are available.
Fields of science
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health scienceshealth sciencespublic healthepidemiologypandemics
- medical and health scienceshealth sciencesinfectious diseasesRNA virusescoronaviruses
- natural sciencesbiological sciencesgeneticsRNA
- medical and health sciencesclinical medicinecardiology
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-AG - HORIZON Action Grant Budget-BasedHost institution
30625 Hannover
Germany