Goal in sight for the London Project to Cure Blindness
Stem cell therapy is a relatively new area of medicine that makes use of the capacity for human stem cells to develop into different cell types. It’s a process that happens naturally in human embryos as they develop, but stell cells can also be grown in a laboratory and implanted into the body to replace faulty cells or organs. The London Project to Cure Blindness, launched in 2007, aims to bring stem cell therapy to treat retinal diseases to the clinic – in particular, for age-related macular degeneration (AMD).
The London Project is based at the UCL Institute of Ophthalmology and Moorfields Eye Hospital and is co-led by Professor Pete Coffey, who works closely with the project’s Clinical Lead, Professor Lyndon da Cruz, Consultant vitreoretinal Surgeon and medical retinal specialist at Moorfields.
The project undertook its first clinical trial in the human retina in 2015; the results, published in 2018, were very positive. Further trials for this revolutionary treatment will start soon, with the aim of gaining regulatory approval for use across the NHS within the next few years.
How did The London Project to Cure Blindness come about?
Replacing organs through transplantation has been well understood for a long time, but the concept of replacing cells with stem cell transplants only began to be investigated in a serious way in 1998. That’s when Jamie Thomson derived the world’s first line of embryonic stem cells – cells from which every other cell in our body can be produced, once you know how the process works.
In 2002, the UK government realised that the concept of ‘regenerative medicine’ had a huge potential for medicine. They took the pragmatic step of investing in the manufacturing of cells to treat diseases, which is what you need to make therapy. In return for doing this, researchers would get access to the stem cells to make use of them for whatever diseases they were interested in, which in my case was the eye. So that’s where my involvement started: trying to figure out how to turn a stem cell into an eye cell.
I came down to UCL from the University of Sheffield in 2005, and in 2007 we set up The London Project to Cure Blindness, helped by a major philanthropic donation. The only thing the donor insisted on was the title – and to my surprise, it’s a name that has become famous all over the world.
What were the original aims of The London Project?
When we launched the project, our main aim was to introduce a new paradigm known as ‘regenerative medicine’. This meant instead of giving a drug to patients, we would try to restore the body’s own biology by bringing it back to a level of good function prior to the onset of a disease – but there was a question as to what diseases this type of approach would be most beneficial for.
One disease we initially targeted was age-related macular degeneration (AMD), a condition that typically affects patients over the age of 65-70. The macular is the central visual area at the back of the eye that essentially contains all the components necessary to process vision, including the cells that respond to light. It's the area you use to read, write and drive, and to recognise family and friends. It contains a layer of cells called ‘retinal pigment epithelial cells’, or RPE. They are not light-sensitive themselves, but are crucial for maintaining the health of the light-sensitive cells at the back of the eye. They do this by making sure they get the right nutrients and support, and by forming a protective barrier to the outside world.
In AMD, the RPE cells start to deteriorate and eventually die, which means the back of the eye no longer has the support it needs, and therefore the cells which do process light start to die as well. Patients with AMD begin to notice distortions in their vision, and eventually lose the sight needed to drive or recognise people. Currently, about 700,000 people in the UK have this condition – about 25% of everyone aged over 70 – so it’s a huge issue for patients and the NHS.
The London Project started out by making a bold statement: within five years, we would go from the bench to clinical treatment in a patient. We didn't do it in five years, but we did it in eight – which is still a lot faster than anyone else! There was a huge amount of work during that period, in terms of the pre-clinical assessment, all the regulatory approvals, making sure the cells were clinical-grade, etc., so it was quite an endeavour.
When did you first succeed in making RPE cells from stem cells?
I was in Sheffield, but working in collaboration with John Greenwood at UCL. Our aim was always to move towards clinically useful cells, and Sheffield was one of the places manufacturing clinical-grade RPE. I visited Harry Moore and Peter Andrews there, who showed me the embryonic stem cells that they’d made clinical-grade, and I noticed there were black spots in the dish. Black cells, which are very rare in the body, are one of the features of RPE. The pupil in your eyes is black because it's a reflection of those cells. Sheffield were about to throw them away, because they thought it was contamination, but I saw the cells in the dish and said “That's the cell type we’re after”. It was pure coincidence that they had made a line of human, clinical-grade embryonic stem cells that spontaneously made RPE. And sure enough, when we took them and modified the process a bit, it gave us enough RPE to use clinically. So it started with an accident – although we've obviously improved the process a great deal since then.
To what extent has the London Project achieved its aims?
The major milestone was in 2015, when we treated two Moorfields patients with AMD with what was a world-first: using stem cells to make new RPE cells, which were then used to replace the ones that had died at the back of the eye. The patients we selected take part in the trial had to meet very specific criteria: they had to have AMD with severe bleeding, and the conventional therapies (injections in the back of the eye) had to have failed, which meant we were allowed to try stem cells instead.
Amazingly, one of those patients, who couldn't even see a book before the operation, was reading 50 words a minute afterwards – and he still is, nearly five years later. It was one of the first stem cell trials of any kind to prove that the concept of regenerative medicine could work. There had been lots of studies using stem cells, but they had always been ‘safety trials’ – they simply showed that there wasn’t a negative outcome. None of them had shown a benefit to the patient, which is the main reason for doing the research in the first place – and that’s exactly what our trial did. In 2018, we published our results in a high-profile journal, Nature Biotechnology, and it created a media storm*. Thanks to that, wherever I go now people seem to know about The London Project.
What were your criteria for judging the outcomes of the trial?
The success of the therapeutic was assessed by our primary endpoint [the main outcome that a clinical trial seeks to test], which was that patients should have a three-line benefit. That means an improvement in the patient’s ability to read lines of letters on an eye-chart (large letters at the top that get smaller and harder to read as you go down). We thought this was a big ask, because the disease was quite severe in these patients. The first patient we treated got a six-line improvement in their vision, and the second patient got a five-line improvement – both well above the primary endpoint. For the first few weeks after the operation, the patients were tested repeatedly, and have come back every year for follow-up tests – so their involvement (and their data) have been crucial for us in establishing the success of the whole endeavour.
What’s next for the London Project?
The goal this year was to test the therapy on a larger group of AMD patients with severe bleeds. We’ve manufactured a therapeutic at the Royal Free Hospital, in Professor Mark Lowdell’s GMP facility [where pharmaceutical products are made that adhere to ‘good manufacturing practices’], and we were planning to complete our ten-patient trial from mid-April. However, that was delayed by the lockdown: when the coronavirus pandemic broke out, Moorfields closed for all non-essential activity, including clinical trials. We now hope to treat the remaining eight patients later this year, which would get us to a position where we can do a ‘pivotal trial’ – a final phase trial in patients. If that’s successful, the next step would be introducing the therapeutic to the NHS. Meanwhile, we’ll soon be publishing the two-year data on the two patients, and probably the four-year data as well.
There is also a global aspect to the London Project: although I'm based mainly at UCL and Moorfields, I’m also Co-Director of the Center for Stem Cell Biology and Engineering at the University of California at Santa Barbara, which is two hours north of Los Angeles. The centre has two other directors: Dennis Clegg and Jamie Thomson (mentioned earlier), who produced the first human embryonic stem cell. The team there are working on new methods for producing a variety of eye cells, not just RPE.
How would you describe the broader impact of The London Project?
The first major impact has been in the clinic. We’ve demonstrated both a procedure that is safe, using cells that are safe, and a tremendous visual outcome for the individual patients with AMD. What we're doing now is scaling up the programme, going through phased clinical trials to ensure a rapid introduction of this therapy to the NHS. It's a platform we’re building with both Moorfields Eye Hospital and the UCL Institute of Ophthalmology, as well as commercial biotech partners. Our aim is to ensure that we can manufacture enough of the therapeutic, which is essential. We also need to deliver it at source, and get enough places to be able to surgically implant it.
The second major impact has been demonstrating a pathway to the clinical use of stem cells for regenerative medicine. We were the first team in the UK to use embryonic stem cells in this way. As a result, it’s now clearer how to take a stem cell therapy to a clinical population, both for other teams trying to do this and for the regulators. There are teams in Cambridge and Cardiff following a very similar, if not identical, pathway to the one we set in place: for Parkinson's disease and for Huntington's Disease respectively. We went through a lot of pre-clinical work to ensure that these therapeutics would be safe, so the regulators are now much clearer in their expectations.
The third impact – which is going to be essential for the paradigm of regenerative medicine – has been establishing a base of scientists who are able to do this work. Not only is the pathway now in place, but we've also trained a huge number of people, in terms of the basic discovery science needed, the preclinical and regulatory pathway, and also the clinical trial process.
How is the London Project funded, and has this evolved over time?
The London Project began with a donation of about £4 million from an American philanthropist on the East Coast, who wants to remain anonymous. That sparked co-funding from another philanthropist on the West Coast, Kirk Kerkorian (famous for owning MGM Studios), who sadly passed away a couple of years ago. Since then, we’ve had major donations from a number of UK groups, including The Michael Uren Foundation (who continue to fund us), the Oak Foundation and The Sir Joseph Hotung Charitable Settlement.
Funding has always been essential to keeping our team together, with all their expertise. It’s allowed us to continue along the path of taking our idea into clinical therapy. We still have people who were with us at our inception 15 years , thanks to continuous funding from multiple sources, both from UKRI (specifically the Medical Research Council) and from charities, including the Macular Society and Moorfields Eye Charity. We’ve also attracted funds from commercial organisations, including big pharma – such as Pfizer – and from venture capital, which we’re building on at the moment.
The project has really captured the imagination of donors. For example, a tech philanthropist in San Francisco, who heard about us on the web, wrote us a check for $100,000. But we also get individuals giving us small amounts for equipment. For example, we got money for a piece of kit that allowed us to view the blood supply in the back of the eye at a resolution we'd never seen before. And those donations are essential in allowing us to take things forward.
What role have Moorfields Eye Hospital and the NIHR Moorfields Biomedical Research Centre played in the London Project?
Although Pfizer originally supported the clinical trials, we’re in the process of transferring sponsorship for all the trials over to Moorfields. Every clinical trial needs a sponsor who takes responsibility if anything goes wrong, so it’s really important. For a big company like Pfizer it’s routine, because it makes new therapies all the time, but for an NHS hospital it’s a major undertaking.
Through Moorfields BRC, the NIHR has allowed us to bring all the separate components together that are actually needed to produce a new medicine – what we call a ‘disease team’. So it’s no longer just about a basic science researcher with an idea; the BRC provides engineers, manufacturers, regulators as well as clinicians, some of whom have also done PhDs. The London Project has hugely benefitted from that environment, and from the people who now have all that expertise.
Have you been involved in any patient and public involvement and engagement (PPIE) as part of the London Project?
There's been a huge amount of involvement with the public – for example, I recently presented the work in Ethiopia, and I've even presented at the Vatican. Lyndon da Cruz and I have both given seminars and lectures all over the UK about what we’re doing, especially for groups associated with macular disease. It’s been great getting out there, discussing the project with families and individuals affected by AMD.
We also had an artist in residence, Adam Hahn, who took photographs of patients with AMD who were starting to lose, or had lost, their vision. He asked them to describe how they saw themselves, and manipulated the photographs to paint their portraits. The paintings, which were exhibited all over the world, were fascinating; they were in black and white, not to be trendy, but because if you lose your central vision, you lose colour vision. There were doctors at Moorfields who could describe the disease exquisitely, but who’d never stood back and thought, “What does that mean visually?”. When they saw the paintings, they could actually see for themselves what patients were seeing, so it had quite a profound effect .
Will the plan to move Moorfields and the UCL Institute of Ophthalmology to a new site affect the work of the London Project?
Over the last ten years, both the Institute and Moorfields have been in a position where they are introducing new therapies that combine the best discovery science, and which need to be put into the clinic. But to make the most of the staff and expertise we’ve built up, we need a new building and new facilities – and that’s something I hope the Oriel project at King’s Cross will deliver . It will allow us to take cutting-edge science and test it an A-star clinical setting. Although we’ve got funding coming in now, we need it to continue to enable Oriel to happen and to accelerate it.