Description of research to be conducted

Much of our new understanding of aortic disease in Marfan Syndrome comes from the development of the Marfan mouse. The discovery that the problematic gene in Marfan Syndrome was that which produces fibrillin 1, a component of connective tissue, allowed for the development of the Marfan mouse. The Marfan mouse has less fibrillin-1 and develops aortic dilation during early adulthood, which progresses onto aneurysm or dissection, exactly like in those who have Marfan Syndrome. As a result of studying Marfan Syndrome at different stages in this mouse, we now realise that the problem in Marfan Syndrome is not due to the person being born with a weaker aorta, but instead is due to changes that develop later on in the persons life as a result of the lack of fibrillin-1.

It now appears that the stress on the aorta as we age together with inflammation that develops within the wall of the aorta later on due to the lack of fibrillin-1 cause the aorta to weaken. This then creates a weaker aorta, which is further damaged. This suggests that treatment with drugs to modify these processes may be useful in reducing complications with the aorta, particularly if treatment was started early.

We plan to look at the effects of treating the Marfan mouse with drugs called statins. Statins are commonly used, relatively safe drugs, originally developed for the management of high cholesterol. These drugs are designed for lifelong therapy. As well as their effect on lowering cholesterol, they have also been shown to have anti-inflammatory actions in ways that may be particularly beneficial to the type of aorta inflammation that develops in Marfan Syndrome.

We will study whether treatment of the Marfan mouse with statins can prevent the development of aorta dilation, and if so, how this is actually achieved. This research will be conducted in RCSI Education and Research Centre in Beaumont Hospital by Professor Mark Redmond in collaboration with Dr Harry Dietz in Johns Hopkins University Medical School, whose team have done much of the current research in Marfan Syndrome.