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Gene therapy is a revolutionary therapeutic technique that uses genes to treat or prevent diseases. There are several ways it can work: by inserting a gene into a patient’s cells to help fight a disease; by replacing a faulty gene that is causing a disease; or by making a faulty gene inactive.
The technique is likely to be of particular value in tackling inherited diseases, but its development is still at the experimental stage. A world-leading team of researchers and clinicians at Moorfields and the UCL Institute of Ophthalmology has been pioneering the use of gene therapy in eye care for many years. Having conducted the world’s first clinical trial of retinal gene therapy in 2007, they have successfully conducted several more trials, with others currently underway or due to start soon. So far, almost 80 patients have benefitted from these potentially sight-saving therapies, and the team’s findings have been widely published and presented internationally*.
Here, we talk to Professor Michel Michaelides about his work translating experimental science into the real world, developing cutting-edge therapies that aim to improve vision and/or prevent or reduce sight loss in patients who often have limited or no treatment options at present.
Could you give a summary of your work developing gene therapies for retinal diseases?
I’m part of a team of Principal Investigators, with Professor Jim Bainbridge at UCL alongside a wider team that includes Professors Robin Ali and Rachael Pearson and Dr Sander Smith at King’s College London. Together, we are supported by ongoing grants for collaboration: to get gene therapies from bench to bedside, primarily for inherited retinal diseases, but also for neovascular age-related macular degeneration (wet AMD) and diabetic eye disease. My role focuses on the clinical side, translating what's developed in the lab into clinical trials and natural history studies* to prepare for clinical trials.
My work primarily revolves around trying to identify the patients most likely to benefit from the therapies, the most effective time-points for intervention, and how to monitor the endpoints (the safety and effectiveness of therapies). Since some of these endpoints are new, we're having to develop new ways of measuring things we haven't previously needed to quantify. At other times, my work involves applying novel methods of analysing the type of data we've been acquiring over time, trying to exploit it to the fullest extent possible.
We're part of only half-a-dozen groups around the world that have a long history of specific interest in, and clinics for, inherited retinal disease. What sets us apart is having a database of tens of thousands of families and individuals – the largest of its kind in the world.
Modes of gene therapy administration
What have been the key achievements of your research so far in the field of gene therapy?
On the experimental side, the key achievement over the last 10-20 years has been demonstrating proof of principle: that gene therapy can be used effectively to treat several dozen inherited retinal diseases. We’ve shown this experimentally in the lab, including in stem-cell derived models in a dish, and this provides the basis from which to translate those treatments into patients. But it’s a long process to get to a trial; it involves a lot of safety testing, exploring dose responses and toxicology.
From a clinical point of view, our main achievement has been establishing large, incredibly well-characterised, genetically proven cohorts of patients with inherited retinal disease. They've had exquisitely sensitive and detailed testing, including cellular resolution imaging. Determining and developing new structural and functional endpoints has been another major success, as well as starting five different gene therapy trials. That was partly based on getting funding from the Medical Research Council and, subsequently, through the formation of the spinout company Athena Vision and then MeiraGTx*.
How important has the large base of patients at Moorfields been to your research?
We've been very much ahead of the curve in demonstrating the importance of natural history studies. There are few units in the world that have sufficient numbers to conduct such studies on their own. And because Moorfields Eye Hospital and its Biomedical Research Centre have invested heavily in genetic testing, we have huge numbers of patients who now have a genetic diagnosis.
Having genetically proven conditions is an absolute prerequisite for gene therapy: you have to know what the genetic fault is prior to attempting to correct it. Thanks to the generosity of our patients, we've been able to establish large cohorts of patients that represent the entire spectrum of disease severity. We then carefully review them over time, longitudinally, and use serial testing to characterise their disease in great detail. This allows us to design the trials, stratify the most appropriate patients, and test the best measures of change. There are more than 300 different genetic eye diseases, so you have to do a lot of bespoke planning to detect potential benefits or safety concerns effectively.
OCT and FAF imaging of patients with different genotypes of molecularly confirmed patients with macular dystrophies, showing the inherent variability on presentation of inherited retinal diseases.
What have been the main impacts of gene therapy on patients in ophthalmology so far?
We've been overwhelmed by the enthusiasm our patients have shown for taking part in the natural history studies, as well as the phase I and II gene therapy trials. One of the principal questions patients ask in clinic is whether there are any trials or studies they could take part in. Luxturna represents the first approved therapy for IRDs and, as such, is a huge landmark. We have started providing this gene therapy to patients with RPE65-associated retinal dystrophy at MEH and GOSH.
In terms of taking ATIMPs [advanced therapy medicinal products] forward to approval, that's an 8-10 year journey from beginning to end, so it’s a long process.
For RPE65, we've completed our phase I/II study and we’ve published some very positive findings.
For achromatopsia caused by CNGB3 phase I/II, we've completed phases I/II of that study and we anticipate the data will be released in late 2020/early 2021.
For achromatopsia caused by CNGA3, we’re in the dose escalation phase of the trial. It’s been a landmark study, in that we've had the support of European regulatory agencies to start recruiting children rather than starting in adults, given the favourable safety profile that we showed in CNGB3.
The fourth phase I/II study that has fully recruited is for RPGR [retinitis pigmentosa GTPase regulator] – the commonest cause of x-linked RP [retinitis pigmentosa] – one of the most severe, rapidly progressive forms of RP. The first data has been shared at ASRS 2020, with further data to be shared in upcoming international meetings. We're already discussing with regulators about a phase III pivotal trial*, and we're in the process of having similar discussions for a pivotal phase III trial for RPE65.
The fifth study is AIPL1, which causes a far more severe form of LCA [Leber congenital amaurosis] than RPE65. It’s incredibly rare (at least 10 times rarer than RPE65), and has a very narrow window of opportunity – less than four years of age (for RPE65, patients can potentially be treated into their 30s). Three children have had surgery to date: one from Tunisia, two from Turkey and a final child from the USA (whose surgery had to be postponed due to the pandemic).
In addition to all these, there is a large pipeline of further trials for inherited retinal diseases, as well as wet age-related macular degeneration, which we'll be rolling out within the next 12-24 months.
Volumetric maps of retinal sensitivity (VFMA plots), in patient with achromatopsia as baseline (left) and follow-up (right).
Aside from the Coronavirus pandemic, are you facing any hurdles at the moment?
One challenge has been that the FDA did not agree to us only dosing in children for the CNGA3 achromatopsia study. They told us that we had to do a dose escalation in adults, even though children may be more likely to benefit, whereas the European regulators were far more open to reviewing the data and having that discussion about the rationale to recruit children sooner rather than later.
Another massive limitation is the richness of our patient base, both in terms of numbers and all the different genetic forms of IRD, which overwhelms our ability to provide a service for everyone.
You mentioned that AMD, a very common disease, is another possible area for gene therapy. How does this compare to inherited retinal dystrophies (IRDs) in terms of impact?
The most effective treatments for wet AMD are repeated injections of anti-VEGF into the eye. They need to be delivered over many years, and that's a huge burden, financially and logistically, on healthcare services and patients. Gene therapy could be used to deliver anti-VEGF in a sustained fashion, where you don't need to do repeated injections. It could be more therapeutic as well, by avoiding the peaks and troughs of a drug, and may be more effective, even for patients who haven't responded well to standard injections.
The idea is to use a viral vector via a one-off injection to deliver the gene that recruits cells in the retina to make the drug. The retina becomes a factory to produce anti-VEGF molecules in a sustained, lifelong way. The route of administration is being hotly debated, and there are several ongoing trials for gene therapy and AMD, which we have reviewed in a recently published paper.
However, while AMD tends to affect people in later life, the vast majority of IRDs will present either in childhood or early adulthood, so patients have decades of poor vision. The impact of IRDs is very poorly understood – and it's gigantic; although they are rare, they affect millions of people globally. And IRDs are now the commonest cause for being registered blind in England and Wales in the working-age population – it's no longer diabetes, because screening and treatments, including anti-VEGF, are now much better.
Has funding for this research mainly been charitable, or have you had commercial backing?
We’ve had funding from many sources: the MRC [Medical Research Council], Wellcome, the NIHR Moorfields Biomedical Research Centre, the National Institute of Health, NEI, the Foundation for Fighting Blindness USA, Fight for Sight, the Macular Society and Retina UK.
We had an MRC DPFS grant for RPE65 and CNGB3, but the MRC made it clear that there would be no more grants awarded for gene therapy in that area. Clearly they can't fund 300 gene therapy trials for IRDs when you're looking at £3-5 million each; it’s not sustainable. Just to manufacture a gene therapy to GMP [good manufacturing practice] standards costs £1-2 million, not taking into account running a clinical trial in several sites: to have approvals in different parts of the world you need to run a trial in Europe, the US, possibly Southeast Asia; the amount of money required is staggering. So funding was one of the main reasons to form a spinout company, Athena Vision, which later became MeiraGTx.
Gene therapy is absolutely of the moment. It’s currently deemed to be very attractive as a platform technology: if you have the right vector, it could potentially be applied to a huge range of therapies. Recent examples of spin-outs that have been bought out by large companies include Nightstar Therapeutics, an Oxford spinout, which was purchased by Biogen, and Spark Therapeutics, which was bought by Roche. MeiraGTx recently concluded a licensing deal for its IRD programme with Johnson & Johnson, so the future for the company looks very bright. The phase III study that we’re taking forward for RPE65 looks very promising, but it’s an iterative process – the timescale for bringing therapies to market is at least 5-10 years.
Do you have any plans to use large data sets and AI in your research?
Yes, absolutely; there are several different strands to that. One of the main ones that Nikolas Pontikos is spearheading, and Andrew Webster, Omar Mahroo and I are involved in, is doing exactly that. It's funded by Moorfields Eye Charity, and is looking in a targeted way at specific groups of patients, examining some of their clinical findings using OpenEyes*, and some of the imaging – OCT or fundus autofluorescence. The aim is to develop a methodology that would allow machine learning and an alternate approach. We're collaborating with colleagues in Japan to undertake similar studies, and collaborators in Singapore have also reached out to us. Our datasets are very valuable in that regard, given the importance of having reliable diagnostics, which require a genetically proven diagnosis.
Aside from your partners in Japan and Singapore, who else are you working with outside of UCL and Moorfields, both in the UK and internationally?
Within the UK we've got a very good inherited retinal disease consortium that was funded partly through Fight for Sight and partly through Retina UK; that functions very well, and involves working closely with Manchester, Leeds, Oxford and Southampton. It’s primarily about applying whole-genome sequencing and whole-exome sequencing* to identify missing genetic causality in IRD. We also collaborate with them on some of our clinical studies, either the natural history studies – prospective or retrospective – or in terms of patient referrals to our gene therapy trials.
In Europe, we work closely with several units, principally in Paris, Ghent, Amsterdam, Madrid, Barcelona and Tübingen in Germany. In the United States, we work with many sites, either for our gene therapy trials or natural history studies. And in Japan we work with the NISO (the National Institute of Sensory Organs) in Tokyo.
There is now an increasing effort to run international, multi-centre, collaborative natural history studies, and we have participated in several. The largest, best-funded of these were set up by Foundation Fighting Blindness USA and we've been principal recruiters to two, prioritising genes that are among the top five causing IRDs. Both of the studies are fully recruited: the first, called ProgSTAR, was for Stargardt disease looking at ABCA4, and there have been more than 20 papers published from it; the second is for USH2A, the commonest gene causing isolated autosomal recessive retinitis pigmentosa (RP) and syndromic RP with hearing impairment (Usher syndrome Type 2).
Cone photoreceptors with confocal and non-confocal adaptive optics scanning light ophthalmoscope (AOSLO). AOSLO imaging allows for in vivo cellular imaging.
Have you been involved in any Public and Patient Involvement and Engagement with regard to gene therapy?
There have been several events over the last five years, including a Retina Day, an AMD Day and a Stargardt Day*. Moorfields BRC was involved in these, and running ongoing events to engage with different patient groups involved in some of our trials. Through our relationship with Janssen (Johnson & Johnson), MeiraGTx is also establishing further public engagement events, and trying to gauge what patients deem to be a significant benefit from our research.
What’s the significance of the UCL IoO/Moorfields partnership in the gene therapy research?
We are one of the few places that have all the expertise in one site, from the bench – including all of the technologies currently being used – all the way through to the trials, the surgery and the advanced endpoints, as well as the Clinical Research Facility.
The critical thing is having individuals that have a foot in both camps, such as Jim Bainbridge, Andrew Webster and myself. It gives you a better understanding of how these organisations function and how to get the best out of both.
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