Stopping life-threatening problems in people with Marfan syndrome

Marfan syndrome is an inherited condition that affects connective tissue, which provides the structural framework that holds the body’s cells in place. One of the most serious complications of Marfan syndrome is caused by weakness of the aorta (the main artery in your body, which carries blood from your heart to your body) and in particular the ‘aortic root’, which is the section at the top of the aorta that connects to the heart. Because the connective tissue that gives the aorta its structure is weaker, the walls of the aorta can start to balloon outwards. This is called a thoracic aortic aneurysm. If it bursts, the result is massive internal bleeding, and often death. The only effective treatment to prevent aortic rupture is open-heart surgery to replace the damaged section of the aorta.

Finding drugs to prevent aortic aneurysm

Common drugs called beta blockers have been shown to slow this expansion of the aorta. But many people with Marfan syndrome also have asthma, which can be made worse by beta blockers. Previous studies had suggested that angiotensin receptor blockers, drugs normally used to treat high blood pressure, might also be able to slow the expansion of the aorta.

So together with the UK Marfan Trust, the BHF funded the AIMS trial, led by Dr Michael Mullen, then at University College Hospital in London. The trial tested whether an angiotensin receptor blocker, called irbesartan, could be used to treat people with Marfan Syndrome, potentially with fewer side effects than beta blockers. In 2018, the trial showed that the rate of expansion of the aortic root was reduced by 30 per cent in the irbesartan group compared with the control group, and that irbesartan seemed safe, even in children. These findings provided much-needed evidence for using irbesartan as an additional treatment for people with Marfan syndrome.

Marfan under the microscope

Although irbesartan was shown to slow down expansion of the aortic root in people with Marfan syndrome in the AIMS trial, it cannot cure or prevent an aortic aneurysm. It was clear that scientists needed to understand more about the underlying biology of Marfan syndrome to find new, effective treatments. We funded an innovative approach used by BHF Senior Fellow Dr Sanjay Sinha and his team in Cambridge to provide new insights.

The team took skin cells from volunteers with Marfan syndrome and turned them into stem cells in the lab. Stem cells can grow into any type of cell to build or repair different parts of the body. Dr Sinha then turned these stem cells into cells that make up the blood vessel wall. Because these cells are from Marfan patients, they make weak connective tissue and they die quickly.

Dr Sinha’s team looked at what was happening inside the cells and made an important discovery. They found that a set of processes in cells (called a pathway) that was thought to be key in the development of aortic aneurysms in people with Marfan syndrome was only part of the picture. There was evidence that a different set of processes might be more important. The team now hopes to use the lab-generated Marfan blood vessel cells to test drugs that target this new pathway, to try and prevent these potentially fatal aneurysms from happening. 

First published 1st June 2021