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PUBLIC RELEASE DATE:
11-Aug-2014

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Contact: Franca Davenport
f.davenport@imperial.ac.uk
44-207-594-3415
Imperial College London
@imperialspark

First gene therapy trial launched for heart patients with mechanical pumps

For the first time in the world, a patient with a mechanical heart pump has taken part in a new gene therapy trial for heart failure at Harefield Hospital, London.

This is the start of a new clinical trial that will assess gene therapy for patients with heart pumps and provide detailed insight on its impact on the heart muscle.

Heart failure occurs when the heart no longer pumps blood effectively and it affects hundreds of thousands of people in the UK. Some individuals with an advanced heart failure can be fitted with a Left Ventricular Assist Device (LVAD), which supports the failing heart and aims to restore normal blood flow.

The LVAD is an electrically driven pump, moving the blood from the left ventricle into the main artery (aorta) so it can circulate the oxygen-rich blood to the rest of the body. Individuals with advanced heart failure who require a transplant may be fitted with an LVAD to keep them alive until a suitable donor heart becomes available. Currently there are around 100 to 150 people in the UK living with an LVAD.

The new trial, led by Imperial College London and funded by the British Heart Foundation (BHF) and Celladon Corporation, will explore whether this gene therapy could help these patients' hearts recover and potentially provide an alternative treatment. It is the first study of gene therapy in this patient group. The work was initiated with support from the Leducq Foundation.

This particular gene therapy is designed to increase levels of SERCA2a protein in heart muscle cells. SERCA2a plays an important role in heart muscle contraction. Genes are inserted into the heart muscle cells to increase the level of SERCA2a using a harmless engineered virus that is based on a naturally occurring virus. In this study the research team will take small biopsy samples of the heart muscle six months after treatment to measure if the gene is present, detectable and functional in the patients' hearts.

Professor Sian Harding, Professor of Cardiac Pharmacology and Head of the BHF Centre of Regenerative Medicine in Imperial College London, who helped develop the treatment, said: "We will be using state-of-the art methods to gain detailed information on how and where the gene therapy takes effect, which will potentially help us develop and improve the therapy. It's important to remember that the therapy is not correcting a gene defect. We are working much more downstream, which means that no matter what the cause of the heart failure, the therapy should be equally beneficial for patients whether their heart problems stem from genes, lifestyle or the environment or a mixture of all of these."

The research team plan to evaluate how this therapy works in 24 patients with advanced heart failure who are fitted with LVADs. Of the patients enrolled in the study, 16 will be treated with the gene therapy and eight will be treated with a placebo. Dr Nick Banner, the consultant cardiologist at Harefield Hospital who carried out the first gene therapy infusion, said: "Advanced heart failure is a progressive condition that results in a poor quality of life and shortened life expectancy. The best treatment currently available is a heart transplant but the shortage of donor organs in the UK means that many patients will die on the transplant waiting list.

"LVADs can keep some patients alive long enough for a donor heart to become available. The rationale for this study is to investigate the effectiveness of a new form of therapy, which might in the future be a viable alternative to transplantation. This study will help us better understand whether the concept of repairing a heart with gene therapy might be possible, even in patients with advanced heart failure. The patients taking part in the trial will have regular tests to see if there are any improvements in heart function."

Lee Adams, 37, from Hertfordshire, has been living with an LVAD for over two and a half years and is on the waiting list for a heart transplant. He is the first patient in the world with a mechanical heart pump to take part in this new gene therapy trial. The LVAD keeping him alive is always connected to an external power supply via a lead through his abdomen. He explained: "It took some getting used to living with an LVAD. You can't just jump in the bath or the shower and it's difficult sleeping whilst being attached to it. Everywhere I go I have to carry the power supply and spare batteries in a backpack."

Lee is hopeful about the outcome but careful not to get too carried away. He said: "Of course the best thing that could happen would be for my heart function to show signs of improvement and for the gene therapy to prove to be a 'miracle cure' for myself and other patients. But I'm not building up my hopes too much because, for all I know, I might have had the placebo. If it does prove to be successful it would be exciting for patients who need a transplant but end up on the waiting list for a long time because of the shortage of donors."

The new study will be the first to evaluate whether gene therapy is delivered to the heart muscle and if its effectiveness is compromised in patients with antibodies to the virus, which delivers the gene.

Previously patients with an antibody to the naturally occurring version of the virus (about 50-60 per cent) have been excluded from a larger ongoing CUPID2 trial, which is investigating the benefits of gene therapy in people with heart failure but no LVAD device. Patients were excluded because it was believed possessing the antibody would render the virus less effective at inserting the gene into the heart muscle. However the actual effect of the antibody has never been explored in patients. This new study will evaluate the effectiveness of the gene therapy in both those patients who have the antibody and those patients without the antibody in order to make a comparison.

"We have adapted the wild virus by removing the viral genes and replacing them with the treatment SERCA gene, so the virus acts like a biological courier to deliver our treatment gene," explained Dr Alex Lyon, BHF Senior Lecturer, honorary consultant cardiologist at the Royal Brompton & Harefield NHS Foundation Trust and trial lead investigator from the National Heart & Lung Institute at Imperial College London. "This particular virus is advantageous because it is not known to cause any human disease. However this means many people have been exposed to the virus without developing symptoms and therefore possess antibodies. If we exclude this group, then potentially a substantial number of heart failure patients would not be eligible to receive this therapy. If we demonstrate that the antibody does not block the delivery of gene therapy, many more patients could benefit."

The 24 patients in the trial, recruited from Harefield Hospital, London and Papworth Hospital, Cambridgeshire, will either receive the gene therapy or a placebo. Six months later a sample of tissue or biopsy will be taken from the heart muscle and examined in laboratories in Imperial College London. This will provide an exploratory analysis of how much of the SERCA2a gene and protein are actually getting into the heart muscle. For those patients on the trial who subsequently undergo a transplant the research team will also then be able to examine the whole heart. This will allow an investigation into how the therapy affects heart function and the underlying mechanisms such as electrical currents, calcium levels and structure of individual cells.

This trial complements the larger ongoing CUPID2 trial, also funded by Celladon Corporation, which is investigating the benefits of gene therapy in 250 people with less advanced heart failure from Europe and the USA, including 14 patients from the UK. Data from the CUPID2 trial is expected in April, 2015.

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There is a fuller written case study available for Lee Adams but he is not available for media interviews.

For more information please contact:
Franca Davenport or Sam Wong
Research Media Officers
Imperial College London
Email: f.davenport@imperial.ac.uk Tel: +44(0) 20 7594 3415
Email: sam.wong@imperial.ac.uk Tel: +44(0) 20 7594 2198
Out of hours duty press officer: +44(0)7803 886 248

Mark Fenwick
Head of media relations
Royal Brompton & Harefield NHS Foundation Trust
Email: M.Fenwick@rbht.nhs.uk
Tel: +44(0) 207 351 8672 Mobile: +44(0) 7866 536 345
Out of hours: a member of the team can be contacted via the hospitals' switchboards on 020 7352 8121

Notes to editors:

1. About Imperial College London

Consistently rated amongst the world's best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment - underpinned by a dynamic enterprise culture.

Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges.

In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK's first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible.

Website: http://www.imperial.ac.uk

2. Royal Brompton & Harefield NHS Foundation Trust is a national and international specialist heart and lung centre based in Chelsea, London and Harefield, Middlesex. The Trust helps patients from all age groups who have heart and lung conditions and is the country's largest centre for the treatment of adult congenital heart disease.

Harefield Hospital is one of the UK's largest and most experienced centres for heart and lung transplantation. The transplant unit has the best long term patient survival rates in the UK. Mr John McCafferty, who had a transplant at Harefield in 1982, is recognised as the world's longest surviving heart transplant patient by Guinness World Records.

Harefield also has the largest number of patients with a Ventricular Assist Device (VAD) in the UK. The VAD team carries out approximately 30 new procedures every year and looks after over 50 patients who are living with a VAD.

In 2013 Harefield became the first transplant centre in the UK to adopt the Organ Care System (OCS) as standard practice for heart transplant procedures. The revolutionary organ retrieval system enables a donor heart to beat outside of the human body before it is transplanted.

Website: http://www.rbht.nhs.uk

3. About Celladon Corporation

Celladon is a clinical-stage biotechnology company applying its leadership position in the field of gene therapy and calcium dysregulation to develop novel therapies for diseases with tremendous unmet medical needs. Our lead programs target SERCA enzymes which are a family of enzymes that play an integral part in the regulation of intra-cellular calcium in all human cells. Calcium dysregulation is implicated in a number of important and complex medical conditions and diseases, such as heart failure, vascular disease, diabetes and neurodegenerative diseases. MYDICAR, the Company's most advanced product candidate, uses gene therapy to target SERCA2a, which is an enzyme that becomes deficient in patients with heart failure. Celladon recently completed enrollment of a 250 patient Phase 2b trial evaluating the efficacy of MYDICAR in reducing the frequency of, or delaying heart failure-related hospitalizations. This randomized, double-blind, placebo-controlled, multinational trial is evaluating a single intracoronary infusion of MYDICAR versus placebo added to a maximal, optimized heart failure regimen in patients with New York Heart Association class III or IV symptoms of chronic heart failure due to systolic dysfunction. The Company has received Breakthrough Therapy designation from the FDA for this MYDICAR program and expects to report results from the Phase 2b trial in April 2015. In addition, Celladon has identified a number of potential first-in-class compounds addressing novel targets in diabetes and neurodegenerative diseases with its small molecule platform of SERCA2b modulators. Celladon is based in San Diego, California. For more information, please visit http://www.celladon.com.

4. British Heart Foundation

Coronary heart disease is the UK's single biggest killer. For over 50 years we've pioneered research that's transformed the lives of people living with heart and circulatory conditions. Our work has been central to the discoveries of vital treatments that are changing the fight against heart disease. But so many people still need our help. From babies born with life-threatening heart problems to the many Mums, Dads and Grandparents who survive a heart attack and endure the daily battles of heart failure. Join our fight for every heartbeat in the UK. Every pound raised, minute of your time and donation to our shops will help make a difference to people's lives. For more information visit bhf.org.uk.

5. About Papworth Hospital

Papworth Hospital treats over 23,800 inpatient and day cases and nearly 73,000 outpatient cases each year from across the UK. It is the largest heart and lung transplant centre, the national centre for pulmonary endarterectomy and a national centre for a range of other specialist services. Since carrying out the UK's first successful heart transplant in 1979, Papworth has established a reputation for leading edge research and innovation.

Papworth Hospital carries out more major heart operations than any other hospital in the UK, currently more than 2,400 per year. With regular scrutiny by robust quality performance monitoring systems the survival rates and outcomes of these operations are among the best in the world. http://www.papworthhospital.nhs.uk

Papworth is a member of Cambridge University Health Partners.



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