Swimming Against the Nucleotides

Rewarding Work

Tomorrow’s cures for retinopathies will likely include advanced gene and cell therapies delivered by precision surgery

Translational research often requires both scientific and clinical input – and this demands collaboration between groups with complementary skill-sets. Developing gene or cell therapies for retinal disease requires sophisticated expertise in a range of disciplines from molecular biology to microsurgery. Close collaboration was critical for the 2017 approval of a gene therapy for Leber Congenital Amaurosis (LCA), which is a form of childhood blindness that can be caused by the lack of a gene called RPE65. The contribution of our team at UCL/Moorfields was recognized last year, when the 2018 Antonio Champalimaud Vision Award was awarded to the four groups working to develop gene therapy for this condition. Working on a new therapy for an unmet clinical need is its own reward – but it’s certainly an honor to receive such recognition!

Playing the long game

My involvement in LCA gene therapy began some 20 years ago, when I began working with Robin Ali at UCL – another of the Award winners – to develop surgical techniques for the delivery of gene therapy to the retina. We were under no illusion that retinal gene therapy would be a quick fix, but the rate of progress surpassed our expectations. The licensing of an approved treatment is an important landmark.

It has not been easy, however; getting to the stage of clinical application required many small incremental steps along the way, as well as a few critical step-changes. At first, we focused on efficient delivery of genes to the retina – solving this problem with AAV (adeno-associated virus)-based vectors was a key development that really enabled us to move forward. AAV is well-suited for gene delivery in the eye, since different serotypes vary in their affinity for different ocular cell types – you have an innate selectivity to play with. Once the delivery step was resolved, we turned our attention to the question of efficacy: what benefit could be derived from delivering functional copies of relevant genes to the retina? We answered this question in a mouse model by demonstrating that injection of a gene into the retina helped rebuild light-sensitive photoreceptor cells – another seminal advance.

Next steps

LCA isn’t the only retinal disorder that could benefit from advanced therapies. About 10 years ago, we started working on gene therapies for other retinopathies – for example, achromatopsia – and three of these programs have now progressed to Phase I/II trials in both the UK and the US. We also intend to target other inherited retinopathies in the future, particularly severe conditions of childhood – partly because of the great need for a therapy for these patients, and partly because younger patients may benefit most from therapies that stop the disease before it progresses too far.

All the while, we should remember that gene therapy won’t be applicable to all patients with retinal disorders – for example, in some the cells are too damaged to be corrected by a therapeutic gene. In these cases, we should consider rebuilding the retina by cell therapy. Regenerative therapies based on stem cells are very promising, and there are a number of active programs in this field. I personally have had some experience of using stem cell-derived material in macular degeneration (1); one of our key findings was that this cell therapy approach appears safe in people with advanced disease.

We’re also looking at ways to transplant photosensitive cells – Robin Ali has been working on that for many years – and we are very excited by recent laboratory results. These include new methods for 3D culture of retinal cells, which mean that we don’t need to grow retinal cells as 2D-monolayers any more – we can culture them in suspension, as spheres with different layers of cells which almost recapitulate the development of the eye. These structures are likely to make excellent models of disease development, and may provide a very useful source of photoreceptor cells for transplantation.

A third critical milestone was reached when we took gene therapy into the clinic and found that it could improve sight in people with LCA.  Media interest was intense - we even had a BBC film crew in theater for the first clinical trial surgery, which made things interesting!

Overall, it has been a wonderful journey, not least because of our patients who have all been trusting, and wholly confident in our efforts to do our very best for them. The patient who had the first surgery was particularly selfless, because he was the first ever to have gene therapy for genetic blindness. For him, the risks were unknown and the chance of significant benefit was small. He understood that we had to go one step at a time; his involvement – and that of others like him – has been critical for the therapy to get as far as it has.

The development of several of our gene therapies has been accelerated by essential commercialization with the founding of a UCL spin-out company and the support of MeiraGTx. The approved gene therapy was developed in the US by Spark Therapeutics and is being used there – it is currently being considered for use in the NHS. At present the drug is very expensive, owing to the high cost of development for this very new therapy, and the hope that it will provide lasting benefit from a single administration. In time, these types of therapy are likely to become more affordable.

A mixed future – in a good way

I am a surgeon by training, and approach translational research from a surgical perspective. Surgery and molecular biology may seem an unlikely combination, but I see it as an amazing opportunity, and feel very fortunate to be in a position to help bring scientific advances into the clinic. I really feel this mixture of skills has the potential to make a huge difference to people’s lives. I think others too are starting to recognize the value of this combined approach.

Consider the actual delivery of the therapeutic genes into the retina. In principle this is straightforward; in practice, it’s challenging. The procedure has the potential to be difficult, or even to cause patient harm, partly because degenerating retina can behave differently to normal retina – for example, it may be relatively fragile. These issues can complicate the precise delivery of therapeutic genes, and must be managed with appropriate care.

We’re very confident that gene therapy will play a significant role in the treatment of inherited retinal diseases, and it is very exciting to see the regulatory authorities recognize the positive data generated by LCA gene therapy trials. Looking further ahead, the field of retinal regeneration by cell therapy is full of challenges and opportunities; it will take longer to get these products licensed, but such an approach may be the best option for many retinal disorders. In many cases, gene therapy and stem cell therapy will be used in combination – we may wish to use gene therapy to modify the patient’s own stem cells prior to implantation, for example. No single approach or single skill set will be sufficient for most inherited diseases of the eye – we need to access a portfolio of expertise if we are to cure the retinopathies.