A zebrafish platform for genetic and chemical screening to improve diagnosis, risk estimation and treatment of cardiovascular manifestations in Marfan syndrome.

Marfan syndrome (MFS) is a rare disease caused by defects in the fibrillin-1 gene (FBN1), typically affecting many organ systems. The cardiovascular manifestations negatively impact life-expectancy, as MFS patients are particularly susceptible to progressive widening of the aorta that may lead to life-threatening tears in the vessel wall. Currently, there is no cure for MFS and clinical therapy is limited to reducing the risk of severe complications. To accurately diagnose MFS, patients are often referred for genetic testing. Based on existing knowledge and available methods, many genetic variants in FBN1 can however not be conclusively linked to MFS. We have recently generated a zebrafish model with a fibrillin defect, which shows an MFS-related cardiovascular phenotype already at the embryonic stage. We propose to capitalize on this model to investigate the biological disease mechanisms. Another main objective is to test the in vivo cardiovascular effects of thousands of chemical compounds, an approach which is feasible in this versatile model. Using this unbiased screening approach, we expect to identify novel drug candidates that would not be found using classical mechanism-based research. Finally, we aim to explore whether the functional effects of human FBN1 can be modeled in zebrafish. This would allow us to efficiently assess the effects of uncharacterized FBN1 variants in vivo so we can support pathogenicity, which will improve clinical management decisions.