From bench to bedside: You can’t have breakthroughs without early-stage research

Her team’s work contributed to a study that recently hit the headlines when it helped four toddlers gain “life-changing” improvements to their vision, regaining the ability to see objects and colour. Born with Leber congenital amaurosis (LCA), “the visual acuity in these children was limited to the perception of light,” Professor van der Spuy said.

Asked about the outcomes of the work, she believes they have been “absolutely amazing.”

But work towards this gene therapy began over ten years ago and involved a long-term collaboration with the clinical team at Moorfields Hospital. It is only just reaching patients. So, what does the journey from bench to bedside really look like?

Small grant; Big impact

The journey toward treatments for vision loss often involves a better understanding of the causes of the underlying condition. In 2014, we co-funded Professor van der Spuy’s Small Grant with Retina UK. The aim was to confirm what changes in a gene called AIPL1 could cause the rare condition LCA.

“If you want to treat a patient by gene replacement or supplementation therapy, you need to be certain that the gene you are replacing or supplementing is indeed the one that is causing the disease,” she said.

“This early-stage research is absolutely vital, not only for developing fundamental understanding of disease mechanisms…but also for developing new therapies.”

Unlocking further funding

While early-stage research is vital for laying the groundwork in clinical research, it also acts as a practical stepping stone for securing future funding.

Professor van der Spuy said: “As an early career researcher, the [Fight for Sight/Retina UK] Small Grant really helped me to advance my independent research career. The publication of our findings, of which there were several, helped open doors to further funding opportunities, enabling me to take my research to the next level.”

Off the back of the Small Grant, Professor van der Spuy was awarded further funding from Retina UK to investigate the disease-associations of mutations in AIPL1.

She was then awarded funding from Moorfields Eye Charity and received a major project grant from the Medical Research Council, allowing her to direct her research towards a pathway which would enable her to translate her research for pre-clinical testing.

Enabling the next step: retina in a dish

Building on the foundations of her earlier research, Professor van der Spuy worked with cutting-edge techniques, including advances in stem cell technologies and gene editing. Crucially, she was able to collaborate with clinical teams at Moorfields Eye Hospital, led by Professor Michel Michaelides and Professor James Bainbridge, to collect patient samples to help her ‘grow’ retinas in the lab for her research. But how does this work?

Professor van der Spuy isolated specific cells in urine samples from young patients aged 1-2 years with the AIPL1 mutations. She then reprogrammed them into what’s known as ‘induced pluripotent stem cells’ or ‘iPSCs’.

“[IPSCs] are genetically identical to the patients from which they are derived, and are very powerful because they can be differentiated or forced to develop into any cell types of the adult human body.”

They then grew these cells into  ‘retinal organoids’ in the laboratory – essentially, ‘retina in a dish’. Because they’re genetically identical to the patients you’re trying to treat, these retinal organoids are an excellent way to test new treatments, including gene therapies.

This allowed Professor van der Spuy to develop the knowledge base essential for collaborating with global gene therapy company, MeiraGTx. This collaboration enabled her team to test the effectiveness of a potential AIPL1 gene therapy in a retinal organoid model derived directly from LCA patients. 

Reaching patients: a key milestone

Professor van der Spuy said: “It's almost impossible to describe the feeling when something you have been involved with for such a long time reaches a stage where it can have a huge impact and make a real difference to people's lives. So, I feel very humbled to have been included and to have been a part of it all.”

As part of this journey, the same gene therapy tested in the patient retinal organoids was applied in the ground-breaking study in LCA patients. The children, aged between 1 and 3 years at the start of the study, received a single injection in one eye followed by a long-term follow-up about three years later to observe the effectiveness of the therapy.

“The gene therapy was impressively effective in the treated eyes, with life-changing improvements in functional vision. What's important to recognise is the untreated eyes showed no improvement whatsoever. In fact, they either deteriorated to unmeasurable levels or lost the perception of light altogether.”

The critical role of early support

Professor van der Spuy is clear: “Without early-stage research, impactful studies such as this would not happen.

“Early-stage research may seem very far removed from a direct application, so I think it's important to highlight and understand that early-stage research underpins the foundational basis from which all further research progresses, which may ultimately facilitate the development of a therapy.

“Many new therapies are experimental. You can't go straight into a patient, so you have to do these early studies to understand how they may work.

“As a researcher, we're very grateful to the charities for supporting us. I wouldn't be here without the early support from Fight for Sight and Retina UK. They obviously play a vital role, and they have a very difficult role as well because it can be very difficult to envision how and if early stage research might progress to an insight or intervention directly beneficial to patients.”

Future aspirations

There are about 30 different genes implicated in LCA and many more in inherited retinal dystrophies, so there’s still much more work to be done. When asked whether the results of this study could offer hope for other paediatric gene therapies, Professor van der Spuy said: “Yes, I would say so. However, you may not necessarily have the same outcome because the gene might be expressed in a different cell type for example, and it will depend on many other parameters of the underlying gene as well such as the size, structure or function.

“With this particular study, all those things seem to have come together for an optimal effect.”

Since this gene therapy has reached patients, Fight for Sight has continued to support Professor van der Spuy’s work contributing to our knowledge of AIPL1 and other genes associated with inherited retinal disease.