Researchers recreate genetic disease in a dish

British Heart Foundation (BHF) researchers at the University of Cambridge have created, for the first time, blood vessel tissues in a petri dish which mimic Marfan syndrome in human arteries.

They have now used these blood vessel models to gain more understanding of how the inherited disease can lead to fatal aneurysms. Their results, which provide insights into why clinical trials of drugs to treat the disease have so far been largely unsuccessful, are published today in the scientific journal Nature Genetics.

People with Marfan syndrome often go on to have a thoracic aortic aneurysm (TAA), where the main artery leading away from the heart balloons and can cause a life-threatening rupture.

Currently the only treatment that prevents aortic rupture for Marfan patients suffering from a TAA is to have open-heart surgery to replace the damaged section of the aorta.

An estimated 13,000 people in the UK have Marfan syndrome, which is caused by mutations in a gene known as fibrillin-1.

The researchers took skin biopsies from two people with Marfan syndrome. They then used cells from these biopsies to create stem cells known as human induced pluripotent stem cells (hiPSCs). They then used these stem cells to create smooth muscle cells, cells which make up the wall of our blood vessels.

Using the blood vessel model, the researchers have already found that the pathway initially thought to be responsible for the development of TAAs in people with the syndrome actually only makes up part of the picture. These findings may explain why clinical trials for drugs acting to disrupt this pathway have proven disappointing so far.

By using the blood vessel models the researchers were able to tell that a separate pathway was, in fact, more critical in causing the aneurysms. The team now hope to use the lab-generated vessel cells to test drugs which target this new pathway for their potential to prevent people with Marfan syndrome from developing a TAA.

Dr Sanjay Sinha, a BHF Senior Research Fellow, who led the research at the University of Cambridge Stem Cell Institute, said: “Our results show that the process behind the development of thoracic aneurysms in people with Marfan syndrome is more complicated than previously thought.

“We now hope to use our newfound understanding of the way that these aneurysms develop to find new drugs to prevent these fatal aneurysms from occurring.”

Professor Sir Nilesh Samani, Medical Director at the BHF, said: “Thoracic aortic aneurysms are a major cause of premature death in people with Marfan syndrome. The only treatment currently available is surgery.

“By creating the first human blood vessel model of this syndrome, these researchers have uncovered a significant new understanding of the disease and provided a new way of testing potential treatments.

“This research brings us closer than ever before to being able to prevent aneurysms developing in people with Marfan syndrome and reducing the need for major heart surgery at a relatively young age.”

Shona Cobb, 19, from Hull, was diagnosed with Marfan syndrome and will likely need open heart surgery in her early 20s. She said: “When I was around eight years old I had an ultrasound scan of my heart that revealed that my aorta was slightly enlarged for my age. I haven’t had a heart operation yet, but my measurements are getting close to the point where they will operate. I am waiting for some MRI results which will tell us more. They think that in my early 20s I will need heart surgery to replace part of my aorta.

“Both my grandad and uncle died very suddenly after developing an aneurysm, so my heart problems definitely play on my mind a lot. It’s reassuring to see that progress is being made that may mean people like me don’t need to undergo such a huge procedure as open heart surgery.”

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