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Gene therapy trials at Royal Brompton Hospital


alexander lyon
The first UK trial of gene therapy in people with heart failure started early this year and was featured on BBC News on 5 September. This is an exciting step into a novel treatment strategy for individuals whose heart failure is progressing despite current treatments.

The trial is called CUPID 2 and is recruiting 200 people from Europe and the United States of America. It follows the American CUPID 1 trial, which was the first clinical trial of gene therapy for heart failure, and showed some promising results.

Lead investigator for the trial is Dr Alexander Lyon, honorary consultant cardiologist at Royal Brompton Hospital and theme lead for advanced heart failure in the NIHR Royal Brompton cardiovascular biomedical research unit.

What is gene therapy?

A gene is a section of DNA that codes for a specific protein. The human genome contains around 20,000 genes that act like an instruction manual to control the function of every cell, tissue and organ in the body.

Gene therapy involves inserting DNA into a cell, causing that cell to produce a protein that contributes to the function of the cell and body organ. This is most easily understood in the context of diseases caused by single gene defects (mutations), such as cystic fibrosis or haemophilia.

In these conditions, people are born with an abnormal gene and if you could insert the normal gene into that person’s cells to replace the faulty gene then they could essentially be cured.

In some people heart failure is caused by a faulty heart gene leading to an inherited or familial cardiomyopathy. In other individuals, heart failure can be caused by heart attacks (blocked coronary arteries), high blood pressure, chemotherapy or viral infections that damage the heart muscle and weaken its pumping strength. In all these diseases the damaged and weakened heart muscle eventually starts to fatigue, and becomes weaker and weaker, leading to the condition we recognise as heart failure.

Research has shown that in the weakened or fatigued heart muscle there are a number of changes in heart genes that appear to drive the deterioration. These changes involve the switching off of some critical genes for normal cardiac function, and this alteration occurs irrespective of the initial cause or damage.

Why might people with heart failure benefit from gene therapy?

Currently, we are not able to turn an individual’s own heart genes back on, but gene therapy involves delivering a healthy gene to supplement one which has been turned off, thereby restoring effective pumping function.

There are a variety of genes affected in heart failure. The particular gene this trial is investigating is responsible for making an important calcium pumping protein called sarcoplasmic reticulum calcium ATPase 2a, known by the abbreviation SERCA2a. The SERCA2a gene is turned off in heart failure, which leads to calcium abnormalities within individual heart cells. Calcium inside the heart muscle cells is critical for maintaining the heart muscle’s pumping power and stabilising the heart rhythm. The calcium abnormalities seen in heart failure contribute to the weak pumping action of the heart and the life-threatening heart rhythm problems that can require fitting of internal defibrillators.

What does CUPID 2 involve?

There are several techniques to deliver genes into cells, but by far the most effective route currently available, and the method used in this trial, is using an inactivated virus.

The particular virus used is called an adeno-associated virus, which is a suitable and attractive option for gene therapy as it efficiently delivers genes into the heart muscle but it is not known to cause disease in humans. It is a common virus, with approximately half the population having been exposed to it without any symptoms. The virus is inactivated so that it can no longer replicate. This is performed by removing the virus’ own genes and replacing them with the relevant human treatment gene.

A coronary angiogram (a thin, flexible, hollow tube called a catheter is inserted into a blood vessel in the groin or arm) delivers the gene therapy, which is injected into the coronary arteries in 10 minutes. It is a single treatment but studies suggest it can have a long-lasting effect.

A small number of people in America had the treatment in the CUPID 1 trial to prove its safety and identify the most appropriate dose. Thirty-seven people received the gene therapy without any safety concerns and some benefit was seen. But a larger trial is needed to really prove if it is effective. This is why the CUPID 2 trial has now started.

Trial centres in the UK

UK recruitment centres are Royal Brompton Hospital, London and the Golden Jubilee National Hospital in Glasgow. Adults are being recruited who have had chronic heart failure for at least six months and have ongoing symptoms despite best current treatment.

Who is eligible for the trial?

To be eligible for the trial people will need to have enlarged hearts that contract poorly. Some people with dilated cardiomyopathy may be eligible, but the trial is not appropriate for people with other inherited cardiomyopathies such as hypertrophic cardiomyopathy.

An initial screening blood test will be required as half of the population have an antibody that inactivates the gene therapy. It is not appropriate to include anyone with the pre-existing antibody in this trial. There may be other research trials that such people could be offered.

Of those who are eligible and decide to take part in the trial, half will receive the gene therapy treatment while the other half will receive placebo (a substance containing no therapy). Neither the medical team nor the individuals in the trial will know which half is which, termed a double-blind trial, to ensure that any improvement in symptoms is due to the gene therapy.

People will be followed up for two years with medical consultations, blood tests, scans of the heart and symptom questionnaires. This information will then determine if gene therapy is effective in improving heart function, reducing breathlessness and fatigue, and reducing emergency admissions to hospital.

Referrals for the trial

If you would like to participate, please contact your GP or local cardiologist and ask them to send a referral to Dr Lyon at Royal Brompton Hospital, with details of your heart failure condition and treatment.

Dr Lyon and his team will then determine your suitability and contact you with the answer.

Royal Brompton

Sydney Street,
London SW3 6NP
Tel: +44 (0)20 7352 8121


Would you like to participate?
Please contact your GP or local cardiologist and ask them to send a referral to Dr Lyon at Royal Brompton Hospital, with details of your heart failure condition and treatment.
Read BBC medical correspondent, Fergus Walsh's report on the gene therapy trial.