A genetic cure for killer heart muscle diseases

Our Big Beat Challenge competition offered the most ambitious research grant in our history: £30m for one project offering a transformational solution to a significant problem for people with heart and circulatory diseases.

The winning project, CureHeart, aims to develop the first cures for inherited heart muscle diseases. It’s led by two world-class scientists: BHF Professor Hugh Watkins from the University of Oxford and Dr Christine Seidman from Harvard Medical School in the USA. They will work with an expert team to develop revolutionary gene therapy technologies to target the genetic faults that can cause these conditions.

Inherited heart muscle diseases, also known as genetic cardiomyopathies, are a group of conditions which affect the heart muscle. They include most cases of hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy, and some cases of dilated cardiomyopathy. The therapies the CureHeart team are developing will be designed to tackle cardiomyopathies in people with a positive genetic test, as they will be tailored to their specific genetic faults. 

Cardiomyopathies devastate families

Inherited cardiomyopathies affect around one in 250 people worldwide. That amounts to 260,000 people in the UK. Many live with these conditions without knowing. Some people have no symptoms. But others can experience life-changing symptoms including shortness of breath, palpitations, and chest pain. Sometimes these conditions can be deadly, with some people dying suddenly from cardiac arrest. Or they can lead to heart failure, and in severe cases people may need a heart transplant. As Professor Watkins says: “Cardiomyopathies devastate families.”

Currently we can help to relieve symptoms or protect against cardiac arrest. But there are no treatments that stop or reverse the progressive damage to the heart, and no cure.

Gene therapy and its challenges

Supported for decades by our funding, Professor Watkins has made important discoveries about hypertrophic cardiomyopathy and the genes that cause it. He also established the UK’s first testing service for the condition. But, he says: “Diagnosis without effective treatment is not enough.”

Developing gene therapies for genetic cardiomyopathies is more complex than for other conditions, and the CureHeart team will face many challenges.

We have two copies of nearly every gene in our body – one inherited from each of our parents. Genes contain instructions that tell our cells which proteins to make. Together, these proteins form the building blocks of every tissue and organ in our body. Gene mutations are like spelling mistakes in the gene: they affect the proteins that are built and can stop parts of our body working as they’re supposed to.

Diagnosis without effective treatment is not enough.

For some other genetic conditions, it’s possible to introduce healthy copies of a faulty gene into the body to help things work normally. But many of the gene mutations that cause cardiomyopathies cause an abnormally shaped protein to be built (dominant negative mutations), and this stops proteins produced by the healthy copy of the gene working – so adding more healthy copies of the gene generally won’t help.

In other cases (haploinsufficient mutations), gene mutations stop the faulty gene working properly, and while the healthy copy of the gene still makes protein, this isn’t enough. Techniques do exist to put healthy copies of genes inside cells, which could work in theory for this type of mutation. But many of the genes that cause genetic cardiomyopathies are too large to fit in the genetic tools (vectors) that are used to carry the new DNA into cells.

The team will have to ensure that the gene therapies only affect heart cells and don’t affect any other cells in the body. They will also need to find a simple way for these to be delivered, for example as an injection into the arm, rather than through a more complicated procedure directly on the heart.

At the cutting edge of science

The team will need to take different approaches to treat the different types of mutation. One option they are testing for dominant negative mutations is gene silencing – “turning off” the faulty copy of a gene, allowing the unaffected copy to take over. But research shows gene silencing only lasts for around six months, meaning patients would need regular injections or medications to keep their faulty gene silenced.

So, the CureHeart team want to develop a one-time gene editing treatment, to correct or permanently switch off faulty genes.

To do this they will be using a revolutionary new technology, developed in 2016 by Professor David Liu at the Broad Institute. Professor Liu, a member of the CureHeart team, developed base editors – tiny molecular machines capable of identifying and correcting a single mutation in the genetic code.

This is our once-in-a-generation opportunity

These editors could be used to precisely correct the disease-causing mutation in a patient. But there are thousands of mutations that can cause genetic cardiomyopathies and developing base editor technology for all of these might not be efficient. So, they will also investigate using base editors to permanently turn off the faulty copy of the gene, allowing the remaining healthy copy to take over.

For haploinsufficient mutations, the researchers are investigating ways to help the one healthy gene produce more protein. They will target sections of the gene’s code that act like dimmer switches, increasing or decreasing the amount of protein it makes.

How long will the CureHeart project last?

The CureHeart project will run for five years. During that time the team will develop and test their genetic therapies. By the end of the project, the team want to have one or more potential treatments that are ready to move into trials in patients.

There are still ethical concerns and regulatory challenges around gene therapies, which the team will spend time addressing. The team know from their work on CureHeart that people with genetic cardiomyopathies are overwhelmingly in support of gene therapies, and patients with these conditions are a key part of the team.

To balance the potential risks, early clinical trials will involve people with the most advanced conditions (whose health is very poor, so any benefits will be valuable). Once they have shown that these treatments are safe and effective, the CureHeart team want to roll them out to people at earlier stages where it will be easier to reverse damage and cure their condition. If used early enough, the team believe they could stop people with these faulty genes ever developing heart symptoms.

It’s only a matter of time until these treatments become a reality

The results of these therapies won’t be passed on to any children the recipients may go on to have, as the treatment will only affect heart muscle cells. This will help to address some of the ethical concerns about the treatments. But it means that the recipients still have a chance of passing the faulty gene to their children, who later might need to receive this treatment themselves.

If successful, this could pave the way for a new generation of treatments for heart diseases, as researchers will be able to apply the same techniques to correct gene defects that cause other diseases.

Professor Watkins says: “There are numerous genes that we know are involved in other, often common, heart and circulatory diseases. If we can get this approach to work, it would usher in a new era where we can treat people by targeting genes.”

In the meantime, he is optimistic about finding a way to end the suffering genetic cardiomyopathies can cause. “It’s only a matter of time until these treatments become a reality. “This funding is our once-in-a generation opportunity. It could change everything for affected families.”

• Read Elizabeth's story of life with arrhythmogenic cardiomyopathy
• Read Thanieth's story of living with hypertrophic cardiomyopathy

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