The CureHeart Project
About 1 in every 250 people is affected by genetic heart muscle diseases, collectively called cardiomyopathy. Approximately 260,000 people in the UK, and 1.5 million in the US, are affected; many are unaware that they may be at risk.
People with cardiomyopathy often live shorter, impaired lives, and develop symptoms that interfere with daily living. They are at high risk of:
- dangerous heart rhythms
- heart failure.
Most people with cardiomyopathy also say that their condition seriously affects their mental wellbeing, and that of their loved ones.
The genetic nature of the condition means that some families lose multiple family members due to sudden death or heart failure, sometimes even in childhood. Family members also have to deal with feelings of guilt about passing on a life-limiting disease to their children, or struggle with decisions about starting a family.
Current treatments are life-long and expensive, and can cause serious side effects, as well as often not working very well. Implantable defibrillators can prevent sudden cardiac death, but they do not improve symptoms or protect from heart failure, the major cause of death in patients.
With rapid advances in genetic testing, the number of known genetically affected individuals is growing; however, diagnosis without effective treatment is not enough.
We must, and can, do better.
We want to be able to offer this generation of cardiomyopathy patients a cure.
We propose to develop genetic therapies that precisely correct the faulty genes in the heart itself, thus providing a new treatment for, and ultimately curing, cardiomyopathies.
Our approach will address the two major ways that genetic faults cause cardiomyopathies:
- Where the cardiomyopathy happens because a fault in one of the two gene copies stops the other from working, we will develop ways to 'switch off' the faulty copy. We have shown that this approach works in mice.
- We will also develop genetic tools to fix a faulty gene, by editing it to correct the sequence of its genes. This work will build on our successful gene editing in mice which have a faulty gene that caused heart damage.
Where having only one working copy of a gene is not enough to prevent cardiomyopathy, we either need to increase the amount of protein made by the one 'good' copy, or fix the faulty one. We are building on advances in gene editing to treat Duchenne Muscular Dystrophy to do this - these approaches have been shown to work in animals, and we want to develop them further.
Clinicians have now identified tens of thousands of affected individuals and families who carry a faulty gene that puts them at risk of cardiomyopathy. This means that scientists and clinicians understand some of the factors that determine which patients are at risk of serious problems, including people who, while well now, are very likely to develop symptoms and need treatment in the future.
We want to build on these advances further to provide a cure, by bringing together a team of scientists who have created innovative molecular tools that can precisely manipulate genes.
We want to use these tools to develop genetic therapies that will prevent cardiomyopathy from getting worse, reverse the disease in patients who are already affected, and prevent the disease from ever developing in family members who carry a cardiomyopathy gene fault.
To accomplish this highly ambitious goal we need to bring together scientists from different backgrounds to overcome a number of technical hurdles and to develop tools that address the different mechanisms through which faulty genes cause cardiomyopathy.
We have made considerable progress. Our team of researchers have already:
- identified the major cardiomyopathy disease genes, and shown how they cause disease.
- worked out when a faulty gene copy prevents the good copy from working, and when having just one good copy is not sufficient to prevent cardiomyopathy: we have shown how this happens, and the consequences on heart muscle function, in cells donated by patients and in animal models.
- we have found the key genetic sequences that control expression of cardiomyopathy genes in the heart and developed precise, innovative ways to switch on, switch off, or change gene expression, and to edit and correct faulty gene sequences.
- we have produced novel tools for delivery of these genetic medicines to the heart that ensure that they work specifically in heart muscle cells.
Our goal is highly ambitious, but it is achievable. To reach it we will use the once in a generation opportunity presented by the Big Beat Challenge to bring together all our work, collective skills and insights, along with those of the patient community, to focus our efforts and energy into one transformative advance – to develop curative therapies for people with cardiomyopathies.
Successful genetic therapy for cardiomyopathies would also open the way to tackle other kinds of heart and blood vessel diseases too: current treatments can't stop the development of heart failure, which today affects 26 million people across the world, with the numbers and costs growing each year.
In the US, in 2012 alone, 2.2% of the population over age 20 received heart failure treatments that cost over $30.7 billion. New findings have revealed that genetic variants are behind common forms of heart failure too, but working out how these variants cause disease, and how to combat these pathways, will be slow and laborious.
Genetic therapies provide a direct and more efficient way to understand and cure these validated, disease-causing faults, helping avoid the dismal outcomes after heart failure. Our program will pave the way to make these opportunities a reality.