Heart failure (HF) is a growing global health crisis, affecting over 60 million people worldwide. It is a leading cause of morbidity and mortality in industrialized nations. Current therapies for HF, while effective in some areas, fall short for specific subtypes of cardiac injury. For example, chemotherapy-induced cardiotoxicity and cardiac manifestations in COVID-19 patients represent emerging HF subforms for which no dedicated treatments exist. These conditions lead to irreversible damage to the heart, marked by cellular remodeling processes such as hypertrophy, inflammation, fibrosis, and apoptosis. The lack of effective therapies for these subtypes underscores the need for a deeper understanding of the underlying mechanisms driving HF.
The REVERSE project aims to tackle these challenges by focusing on circular RNAs (circRNAs), a novel and promising class of noncoding RNAs with critical roles in cardiac health and disease. CircRNAs have shown potential to reverse pathological changes in the heart, offering a groundbreaking avenue for therapeutic innovation. By developing circRNA-based therapies, REVERSE addresses unmet medical needs and improve the lives of millions suffering from HF.
The project pursues four key objectives:
1. Discovering Therapeutic Targets: Using advanced technologies, REVERSE will identify circRNAs involved in heart remodeling and damage caused by chemotherapy or COVID-19. By screening human cardiomyocytes with a CRISPR-Cas system designed specifically for circRNA silencing, researchers aim to uncover therapeutic targets that can reverse these processes.
2. Validating in Living Human Heart Tissue: A unique feature of REVERSE is its use of living human myocardial slices. This cutting-edge model preserves the heart's natural architecture and function, allowing researchers to study circRNAs in an environment closely resembling the human heart. This approach provides highly relevant insights into the therapeutic potential of circRNAs.
3. Uncovering Mechanisms of Action: Understanding how circRNAs work at a molecular level is crucial for developing effective therapies. REVERSE combines bioinformatics, proteomics, and advanced sequencing techniques to map interactions between circRNAs and their targets. This knowledge will pave the way for precision therapies tailored to specific HF subtypes.
4. Developing Targeted Delivery Systems: The project focuses on creating safe and effective delivery systems for circRNA-based therapies, including lipid nanoparticles and next-generation adeno-associated viruses (AAVs). These technologies ensure precise targeting to cardiac cells, minimizing side effects and enhancing therapeutic efficacy.
