Repairing genes that cause a loss of central vision and an inability to see in full colour

Meet Matteo Rizzi and Kate Powell, the husband and wife team who are working on gene therapies to repair light-sensitive cells in the eye.

They jointly run the Visual Perception and Repair Laboratory at the UCL Institute of Ophthalmology and Francis Crick Institute and are working on developing gene therapies for a rare, inherited condition that deprives those living with it of their central vision and means they can only view the world in shades of grey.

The condition, achromatopsia, is a form of colour-blindness that is present from birth. Kate stresses how this is different from what we commonly understand by what it means to be colour-blind:

“Achromatopsia is a profound loss of cone photoreceptor function as opposed to the more colloquial ‘colour-blindness’ where there is a small change in how the cells work. In the latter, more common condition, you're less sensitive to colours, but you still see some colour.” 

“This condition has a big impact,” adds Matteo.

A loss of central vision

He explains that the condition causes light aversion (sometimes called ‘photophobia’) and a loss of central vision, which makes it difficult for people to read and to recognise faces. 

“It is one of those conditions where there will be minimal or no function in the central part of the retina from birth,” adds Kate.

Achromatopsia is often misunderstood

“I remember meeting one of these patients who was about 50. He shared how frustrating it was to convince people that he had this problem. When we talk about colours, it comes so natural to us to think that everything has a colour, and he shared the pain of experiencing people, even friends and family, thinking he was making up the inability to see an object’s colour.”

“It is a story that reminds me of how important it is to listen to the patient and how difficult it is for these conditions to be understood by others.”

Working in partnership with patients to find solutions for vision loss

The husband-and-wife team say that studying achromatopsia patients was a milestone in their careers.

Matteo said: “Achromatopsia patients were the first patients that Kate and I ever tested when we started taking our first steps in testing patient vision. And that was very transformative because before we had only worked in a lab and had never met patients.”

“We learned that speaking to them, understanding exactly what's wrong with their vision, can be very, very powerful to design our experiments in the lab and then also to design therapies.”

Their focus is on developing gene therapies, and working with patients first-hand has helped them avoid missteps along the way, said Kate.

“With another gene therapy, that we are still developing, there was one moment where testing patient vision completely reversed the way we were thinking about the disease mechanism and how people experience perceptual changes. This really opened the way for us to develop a therapeutic intervention”, she said.

“That was a huge eureka moment for us. And we both said we would never go back to not involving patients in our research, because of how informative and powerful it was, and how close we came to making a scientific mistake without having that information.”

Advancing our understanding of achromatopsia

The lab is working to better understand what causes achromatopsia and to develop gene therapies, which could reach patients in as little as five to ten years.

“We called the lab: 'Visual Perception and Repair' because those are very much the two interests we have. The first part is understanding what's wrong with vision when there is a disease affecting the eye.

"And then the second part is the repair. We try to design therapies to repair cells, with a focus on gene therapy.”

Achromatopsia is a genetic condition that affects the light-sensitive cells that allow us to see colour, called ‘cones’ because of their shape. They have a high density in the centre of the retina, and this density is where we get our high-resolution vision from.

Patients with achromatopsia have genetic variants that cause poor function in cones. This means that they can’t use the central part of the retina, and they don’t see in colour at all.

“This is really a profound loss of cone function as opposed to the more colloquial ‘colour-blindness’ where there is a small change in how they work,” said Kate.

Developing gene therapies

The lab’s aim is to develop gene therapies that can repair cones and other cells in the eye.

“In the beginning, much of the work was to try and understand the mechanism that explains why this happens. From that, we expanded towards thinking can we also study more precisely the patients’ vision, to see, for example, if there actually is a tiny bit of residual colour vision in these patients. Also, can we design a gene therapy for this condition?” said Matteo.

“When clinicians speak to adult patients, they want us to be able to restore high-resolution vision so that they can drive. For children, they want to see colours,” said Kate. “Colour is a really important thing for children in terms of toys and drawing.”

Learning from other eye conditions in the lab

The pair also studies other eye conditions, among them Stargardt disease, for which the lab has received funding from Fight for Sight. “Each condition is very different, of course, and it's important to understand it in detail, but there are some common traits and often that's very helpful. Essentially, this means that, by taking part in research, patients with one condition can also help patients with another.” said Matteo.

For example, Stargardt and achromatopsia both impact the central retina.

“We found an interesting parallel because we found that if cones in this part of the eye are not functioning either in Stargardt or achromatopsia, a very similar consequence happens, which is the light aversion that we've been talking about.”

Kate adds: “It essentially gives us a scientific clue as to where the perceptual effect comes from because we know there are common denominators in these two diseases, even though they have completely different causes genetically.”

Gene therapies on the horizon

Gene therapy is another area of overlap and is a focus of future treatments for both achromatopsia and Stargardt’s.

“Achromatopsia is a condition for which we and others have designed gene therapies,” said Matteo. “One aspect that we're focusing on is making gene therapy vectors, the particles that carry the gene therapy in the eye, even safer and cheaper,” he added.

“It's important to reach as many patients as possible and to make these medicines affordable. Making these little particles cheaper to produce means that the cost of the therapy will be lower and therefore more likely to be available for everyone with achromatopsia and other rare conditions.”

Vision research: a pioneering field

Vision research is a pioneering field in this type of therapy – as Kate said: “The eye is very amenable to gene therapy, partly because of its self-contained nature. It's been a fantastic place to trial gene therapies and so much progress has been made with the ocular gene therapy trials, just in terms of understanding how to dose effectively.”

As for the day-to-day, working as a husband and wife team suits them both.  “We've worked together for nearly 20 years. Two minds are certainly better than one, and we can be honest and open with each other about what we think is good (and particularly what is bad!) in each other's ideas.”

Matteo agrees.  “The first question people usually ask us is if we talk science at home. Of course, the answer is yes, we do! But it happens more if we don't spend the day together and it becomes a bit of a catch up on things.”

But they can’t do it alone, as Matteo said:

“The lab certainly isn’t just Kate and me. There is a team of 10 people now, each responsible for different aspects, and hence it is very hard to replace them. That’s why keeping bright minds in labs, who can be creative and come up with new ideas is very important. People are the most important ingredient of good science, and it’s thanks to funding that we can keep great young scientists in the lab!”