Pushing Boundaries in Pre-clinical Aortopathy Research (BREAK-OUT)

Thoracic aortic aneurysm (TAA) entails a high risk for aortic dissection and rupture, which is a prominent cause of death in Western countries. Prophylactic surgery significantly reduces the mortality risk, but complications are relatively common. Moreover, in severe TAA conditions aneurysms often develop at other locations afterwards, exposing patients to repeated surgeries and, thus, threats.

Current drug options only modestly slow down dilatation, without preventing dissections or ruptures. Clearly, a game changer in TAA patient management would be the availability of medical therapies capable of stopping or reversing aneurysm formation. Functional characterization of the known TAA genes, especially those that are linked to syndromic TAA, in relevant cell and/or mouse models has already delivered valuable insights into the disease mechanisms, prompting pre-clinical drug testing in mice. The mechanistic picture is incomplete though, encumbering the development of additional, and especially more effective, therapies.

Another prevailing issue is the inefficient and/or unsuccessful translation of pharmacological mouse results to the clinic. Few compounds make it to clinical trials due to the high costs, lengthy time frames and difficulties as to patient recruitment. Additionally, while TAA mouse models allow us to study and therapeutically target disease in an in vivo setting, efficiency of ensuing compounds might not be recapitulated in humans.

Building on intriguing preliminary data and the unique availability of mutant/control Fbn1 and Ipo8 mice and human induced pluripotent stem cells, this project aims to contribute to the resolution of these issues by further unravelling and therapeutically targeting the mechanisms underlying syndromic TAA. Additionally, BREAK-OUT will provide proof-of-concept that patient-derived aorta-on-a-chip models can be used for pre-clinical TAA research.