Circular RNAs to reverse pathological remodelling of the injured heart

Introduction

Heart failure (HF) is a most common cause of mortality with currently >60 million 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.

Focus of the Research

We will here focus on noncoding circular RNAs (circRNA) involved in two distinct forms of cardiac injury:

1. Chemotherapy-induced cardiotoxicity
2. SARS-CoV-2 infection

Currently, no specific treatment strategies are available to reverse disease pathology.

Previous Studies

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.

Importance of circRNAs

Within the family of non-coding RNAs, circRNAs are stable and species-conserved, making them ideal drug targets. We discovered multiple molecular circRNA signatures during the remodelling of cardiac cells and tissues from mice and patients.

Research Objectives

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.
d) Perform targeted cardiac delivery approaches of selected candidates in both chemotherapy-induced cardiotoxicity and SARS-CoV-2-induced cardiac disease models.

Methodology

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.

Conclusion

REVERSE aims to discover fundamentally new therapeutic entry points for two forms of cardiac injuries, where currently no disease-specific treatments are available.