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Hope for first drug treatment for life-threatening aneurysms

The first drug treatments for deadly aneurysms in the body’s largest blood vessel could be on the horizon, according to research led by the University of Leicester.

An international team has found that mimicking the effect of drugs used to treat people with high cholesterol can slow the development of potentially catastrophic abdominal aortic aneurysms (AAA).

The researchers, led in the UK by Professor Matthew Bown at the University of Leicester, hope the discovery could lead to clinical trials of the drugs in people with an AAA within the next few years, putting an end to the long wait for a treatment for those living with the condition. Part-funded by the British Heart Foundation, the findings have now been published in Nature Genetics.

An abdominal aortic aneurysm is a balloon-like swelling in the abdominal section of the aorta, which carries blood away from the heart and around the body. There are currently no treatments that can stop an aneurysm developing or growing. If an AAA becomes too large, it can burst causing massive internal bleeding. Around 80 per cent of people with a ruptured AAA die and the condition is responsible for over 2,200 deaths in the UK each year.

Now, researchers have found that drugs called PCSK9 inhibitors, which are already used to treat people with high cholesterol, could be repurposed as a treatment for people with an AAA.

Professor Matthew Bown, British Heart Foundation Professor of Vascular Surgery at the University of Leicester, said: “Despite being relatively common, the only option we can offer patients with AAA is regular monitoring potentially followed by surgery if their aneurysm becomes too large.

“An effective treatment that could slow or even stop an AAA developing would be a huge breakthrough for people living with the condition. But, so far, this has proved elusive. We’re hopeful that our findings can provide the foundation to propel us towards the first drug treatment for AAA.”

PCSK9 inhibitors work by stopping the breakdown of cholesterol receptors, boosting the body’s ability to remove LDL cholesterol (a type of ‘bad’ cholesterol) from the blood. They’re used to treat people with genetic conditions which cause them to have very high cholesterol levels, or those who are already taking medication but whose LDL-cholesterol remains high.

The researchers first performed a genome-wide association study, searching the DNA of over 39,000 people with an AAA for genes that could be increasing their risk of developing the condition. From this, they identified 141 genetic variants involved in the development of aneurysms – including 97 never previously linked to the condition.

One of the genes they identified encodes the PCSK9 protein. The team also found that having higher levels of the PCSK9 protein was associated with an increased risk of AAA.

Finally, the team found that aneurysms grew more slowly when the PCSK9 protein is missing, suggesting that inhibitor drugs could be an effective treatment to slow AAA growth.

The researchers say that the huge number of new genes they have identified, and the biological processes they are linked to such as blood vessel development and inflammation, can also help to guide the search for more treatments for AAA. By focusing on existing treatments known to affect these processes, they hope it might be possible to repurpose more drugs as treatments for AAA.

Professor James Leiper, Associate Medical Director at the British Heart Foundation, said: “The consequences of an abdominal aortic aneurysm bursting are catastrophic and, more often than not, this will cost a patient their life. People with an AAA live day-to-day with this looming threat.

“Repurposing drugs which have already been shown to be safe and effective, such as PCSK9 inhibitors, can dramatically shorten the time it takes for findings to go from discovery to patient trials. While testing in large groups of patients will be needed before these drugs can be recommended, these promising results offer hope to thousands of AAA patients that their long wait for a treatment may soon be over.”

This research was also funded by Health Research Council of New Zealand, Veterans Administration Office of Research and Development, Tobacco-Related Disease Research Program and the National Institutes of Health.

 

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