Marfan syndrome (MFS) is a rare genetic disease, affecting an estimated 1:5,000 to 1:10,000 people. It is caused by defects in the FBN1 gene, which codes for the fibrillin-1 protein. This protein plays an important role in the structure and support of many different tissue types and organs throughout the body. Therefore, MFS can cause a range of symptoms affecting the skeleton, the eyes, and particularly the heart and blood vessels. MFS can lead to a widening of the aorta, the biggest artery in the body, as well as tearing and eventually catastrophic rupture of this blood vessel.
To date, no cure exists for MFS, and patients can only be treated symptomatically by surgery or blood pressure-lowering medication. On the other hand, the consequences of a new sequence variant in the FBN1 gene which is identified during genetic testing cannot be predicted for each patient based on the currently available information. Changes in the FBN1 code might have no effects, could lead to mild or moderate symptoms, or might even cause a quick progression to life-threatening conditions. The lack of effective targeted therapy for MFS, as well as the uncertainty regarding the course of the disease places a heavy burden on the quality of life of MFS patients, and increases the costs for clinical management.
In order to address these issues, there is a strong need for flexible models of MFS which can mirror the complexity of this disease. Mouse models already exist but they are limited by the number of conditions that can be tested efficiently. Zebrafish have been used more and more in preclinical research, since the effects of many different drugs or genetic manipulations can be tested rapidly in this model. The overall goal of this project is to generate a new zebrafish model for MFS, in order to boost the development of a more personalized approach to the management of the disease. More specifically, the main objectives of the project are to validate the new zebrafish MFS model, to develop an innovative system to test the effects of specific human FBN1 gene defects in the zebrafish model, and to use a novel approach to test a large number of pharmaceutical molecules in this model in order to discover new treatment options for MFS patients.
Another important objective of this project is to foster the career development of the MSCA researcher. A major advantage of the interaction with the mentor, a clinician, is the strong link to the clinical aspects of MFS. This helps to clearly identify areas of research which have a strong relevance to patient care, and therefore have a great potential to realize maximal impact beyond the scope of the fundamental research project.
At the end of the MSCA project we have been able to validate a new zebrafish model of MFS, and we have uncovered the specific roles of the different zebrafish fibrillin genes in the cardiovascular system.
