3D-smooth muscle cell assay to identify pharmacotherapy targets for Marfan patients

The AMC and OcellO aim to set up a Marfan patient derived cellular assay to develop personalized pharmacological treatment strategies for the future.

Marfan Syndrome patients have a mutation in fibrillin-1 (FBN1), leading to aortic rupture, causing disabilities or death before the age of 40 years. Marfan Syndrome prevalence is approximately 1:5,000, so actually relatively common. There are only surgical treatment options that prevent aortic rupture, while blood pressure medication can just postpone it. No other drug treatments are available at this moment.

Approximately 2000 different mutations in this FBN1 gene are known to cause Marfan Syndrome, explaining the wide variation in Marfan disease severity. In spite of this diversity, Marfan patients are currently in the clinic considered a uniform group and treated as such. Based on genetic criteria, there were at least two Marfan patient subtypes with distinct aorta disease revealed, responding differently to pharmacological treatment. Currently, these two different genetic subtypes are not understood. In the proposed fundamental research project, the AMC and OcellO will together develop a patient-specific smooth muscle cell 3D-culture assay to study these differences on Marfan aorta smooth muscle cell morphology to find differential drug sensitivity. By using patient cells rather than mouse models, it is anticipated that by screening at least 100 different Marfan patients, different groups of Marfan patients will be discovered that require different medications to normalize their smooth muscle cells shape and behavior.

A novel 3D smooth muscle cell culture assay from Marfan and control patient cells will be delivered; a method for in vitro phenotypic classification of Marfan subtypes; results on drugs that revert or favorably influence the Marfan smooth muscle cell phenotype. With these new insights and drugs, novel patient intervention studies will be set up to ensure that Marfan patients will require minimal hospitalization in the future.