Cardiac Splicing as a Therapeutic Target (CASTT)

• Michael GOTTHARDT, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC) (Germany)

• Leslie LEINWAND, The Regents of the University of Colorado (USA)

Cardiovascular disease is the most common cause of death worldwide, but despite improved prevention and therapy, the incidence of heart failure continues to rise. The most severe forms are genetic and include mutations that affect the protein makeup of cardiomyocytes through a mechanism called alternative splicing. This can result in impaired filling, contraction, and sudden cardiac death. Alternative splicing determines which mature RNA transcripts drive the mechanical, structural, signaling, and metabolic properties of the heart. Here, we will utilize advances in RNA sequencing technologies to study cardiac splicing in mouse, python, human engineered heart tissue and patient samples, paired with targeted network and functional analysis. The resulting splice regulatory network will provide a basis for the identification of novel drug targets and to identify disease-related and disease-causing alternative splicing events in cardiomyopathy. Translating our findings to improve patient care, we will study how alternative splicing is regulated in the heart and how it contributes to cardiac adaptation in the developing mouse embryo and during exercise. As a model for ‘exaggerated’ hypertrophy and regression we will rely on the python, which will allow the identification of proteins with central roles in the regulatory network that cause the strongest physiological effect. We will compare alternative splicing in such models of healthy adaptation vs. disease to improve personalized diagnosis and therapy of heart disease. Taken together, we will assemble a cardiac splice regulatory network that can be mined for novel therapeutic targets, establish a translational pipeline to evaluate splice modulators in human engineered heart tissue and animal models and provide the scientific community and health professionals with resources to facilitate the acquisition and interpretation of splicing data as a basis for improved clinical decision making and patient care.