Inherited pediatric cardiomyopathies: towards a personalized therapeutic approach

Project summary

Cardiomyopathy comprises a spectrum of diseases of the heart muscle and can affect all ages. Here we will focus on cardiomyopathy that arises in childhood. The majority of genes described in adults also contribute to
cardiomyopathy in children. In addition, pediatric cardiomyopathy can be part of various malformation syndromes, neuromuscular disorders and metabolic conditions. Despite advancing sequencing technologies, a substantial proportion of cases remains unexplained. We expect that numerous genes implicated in pediatric cardiomyopathy
still await discovery, each explaining only a small proportion of cases.

Because the prevalence of pediatric cardiomyopathy is low, studies in humans will lack sufficient statistical power to confirm genotype-phenotype
associations. We believe that zebrafish provide an excellent model system to validate and functionally characterize candidate disease genes for pediatric cardiomyopathy.

Zebrafish (Danio rerio) offer a number of genetic and experimental advantages for studying cardiovascular development and disease. Zebrafish embryos are externally fertilized and virtually transparent, allowing in vivo
imaging of heart and blood vessel formation and patterning from an early stage. Their transparency also enables the use of transgenic lines expressing fluorescent proteins in the heart in order to visualize cellular dynamics
during embryonic development. Cardiac development and function in zebrafish show remarkable similarities with those in humans. Several mutant zebrafish lines for known cardiomyopathy genes have already been established.

In this research project we will combine the advantages of zebrafish with the powerful CRISPR/Cas9 technology to generate patient-specific in vivo models of pediatric cardiomyopathy. The established zebrafish models will be used to gain further insight into the underlying pathophysiological processes by combining transcriptomic, proteomic and metabolomics analyses. Deeper understanding of the disease and its associated networks and pathways and subsequent compound screening experiments in zebrafish mutants will help to identify potential drug targets. Our ultimate goal is to accelerate the development of personalized therapeutic interventions for pediatric cardiomyopathy that correct the underlying disease mechanisms in a preclinical stage, thereby preventing cardiac remodelling.