Drug repurposing in vascular Ehlers-Danlos syndrome by using multi-OMIC signatures in human fibroblasts

Vascular Ehlers-Danlos Syndrome (vEDS) is characterised by extreme fragility of arteries and hollow organs, which can rupture spontaneously at an early age, and defective healing process. The diagnosis of vEDS is only possible through molecular analysis, which reveals a mutation in the COL3A1 gene in the affected individual. Detecting vEDS before life-threatening complications is difficult because many affected individuals do not have any pecualiar physical characteristics. Treating vEDS is a very difficult task. In fact, arterial abnormalities are rarely detected before rupture, and surgery has very limited efficacy. The best solution for improving the life expectancy of those affected is thought to be the identification of drugs that can prevent arterial ruptures. Unfortunately, vEDS remains without a cure to date. Our preliminary study of vEDS perfomed on patient cells identified several signalling pathways that are altered in patients compared to healthy individuals. In this project, we propose to use our preliminary data to define a cellular phenotype of vEDS that will be used as a signature to select drugs capable of correcting the defects identified in vEDS cells. More specifically, we aim to explore potential benefits by exposing affected tissues with hundreds of drugs that have already received FDA/EMA approval. The therapeutic potential of drugs identified as modulators of pathological cellular phenotypes will be evaluated in vEDS fibroblasts. We hope that obtained data will stimulate the generation of clinical trials in humans.