Abstract
Thoracic aortic aneurysm (TAA) denotes a progressive enlargement of our body's largest artery, i.e. the aorta. It frequently remains unnoticed until aortic dissection and/or rupture occur, which are associated with high mortality rates. Although prophylactic aortic surgery can serve as a lifesaving event, it comes with important risks. Current drug therapies can only slow down TAA progression to some extent, but cannot fully prevent aortic dissections/ruptures. Better therapeutic options are clearly needed. TAA and the ensuing aortic complications are a hallmark of a rare connective tissue disorder, called Loeys-Dietz syndrome (LDS). While LDS-related TAA is relatively understudied as compared to other TAA conditions, it is an important study case considering its early onset and aggressive disease course. Taking advantage of the advent of the iPSC technology and our expertise in clinical and pathophysiological LDS research as well as iPSC-vascular smooth muscle cell and iPSC-endothelial cell disease modelling, we want to significantly expedite bench-to bedside translation of LDS research by developing and functionally validating iPSC-derived aorta-on-a-chip (AoC) models of TAA-presenting patients and isogenic controls. Upon demonstration of the known pathomechanisms and drug responses in SMAD3 mutant AoCs, we will investigate if our AoC models can also recapitulate between-patient variability in disease severity. In conclusion, we here take up the challenge to develop a novel pre-clinical tool allowing exploration and therapeutic targeting of LDS mechanisms in a human setting that more closely resembles the native aorta than ever before. The anticipated results will prove relevant for TAA in general, as the AoC expertise that will be acquired within the frame of this project can immediately be translated to other TAA conditions.
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