Seeing is believing

"Blindness in Australia is a fixable problem," says Professor Peter McCluskey AO, Director of the University of Sydney's Save Sight Institute at Sydney Eye Hospital and an inflammatory eye disease specialist of international standing. "About half a million Australians have severe vision impairment, and up to 90 percent is preventable or treatable."

Beyond the human cost of impaired vision, there are costs to the health system and to the broader economy. As just one example, inherited retinal diseases alone cost Australia an estimated $780 million to $1.56 billion per year.

New insights and technologies developed over the past few years have seen a dramatic expansion in the therapies available to the leading ophthalmologists, researchers and scientists of the Save Sight Institute. Their work has them rated sixth among eye research groups globally.

Peter started his career as an ophthalmologist on the frontline of the AIDS crisis, tackling a viral eye infection that often strikes people affected with HIV-AIDS. "I was part of a multidisciplinary team that made a couple of HIV treatment breakthroughs," he says. "It was an incredible learning journey, and the foundation of the work I do now."

Beyond his duties as director of the Save Sight Institute - a flagship research centre within the Faculty of Medicine and Health, Peter is also a researcher, an educator, and a clinician working out of two Sydney eye clinics. He also runs outreach clinics - one in Tasmania and another in the Northern Territory - where he works to improve the services available to Aboriginal people living in isolated locations.

While immunology was the new frontier early in Peter's career, genetic medicine is the new frontier today, having been supercharged by the mapping of the human genome. That process took thirteen painstaking years, but gave us the first complete picture of human DNA molecules and the genes they contain.

"Now it's a case of not being able to see the forest for the trees," Peter observes. "We can see all these genes, but there have to be some master pathways. We have to find those upstream regulators that control these pathways."

Genes guide how our bodies grow and behave, and malfunctioning genes are the cause of numerous conditions, including more than 350 that disrupt vision. In the rapidly evolving discipline of genetic medicine, Professor Robyn Jamieson could be described as an early adopter, since she became interested in the potential of genetic medicine long before many others realised it had any value at all.

Robyn is Head of Genomic Medicine at the University of Sydney, as well as Head of the Eye Genetics Research Unit at the Children's Medical Research Institute, Sydney Children's Hospitals Network and Save Sight Institute. She began her career studying paediatrics, and was inexorably drawn towards clinical genetics, with extension through a basic science PhD in Sydney and then a genomics postdoctorate in the UK.

"I remember in the late '80s someone in a lecture theatre talking about the first disease-causing genes that had been identified," Robyn recalls. "Hearing that was a real lightbulb moment for me, because I was treating all these kids who had various symptoms, but we had no idea what was causing them."

A lot has changed and is still changing. In what is a true triumph of genetic medicine, there are now various methods, both existing and in development, whereby a malfunctioning gene can be identified, located and replaced or edited to produce a healthy gene.

It's easily said, but tremendously difficult to achieve - though Robyn first did exactly that in 2020. She was managing a genomic investigation into people born with Leber congenital amaurosis (LCA), a type of retinitis pigmentosa that compromises the function of the retina as it converts light into electrical signals that our brains in turn convert into images. LCA causes vision impairment from an early age, so that some children may not be able to walk without a cane to guide them. The cause in some cases is a malfunctioning RPE65 gene, which provides instructions for making a vision-related protein. If it doesn't, it can trigger a range of retinal problems, including LCA.

Fortunately for the people affected, the only genetic treatment currently commercially available, Luxturna (Novartis), specifically treats mutations of the RPE65 gene. And thanks to a longstanding collaboration between the Save Sight Institute, the Children's Medical Research Institute and the Sydney Children's Hospitals Network, Robyn was able to lead a team to begin the process of confirming people's suitability to receive the treatment and delivery of this gene therapy. This included laboratory research to undertake the months-long process for two young siblings, using their blood-derived stem cells to grow mini-retinas in a dish and observe the action of the gene. The results showed that they were suitable for the treatment.

The mechanism used in RPE65 gene therapy involves a neutralised virus with a healthy replacement gene attached, which is injected into the eye so that the virus can carry the healthy gene to where it's needed. Once there, the healthy gene takes the place of the malfunctioning gene.

For the eight people treated so far, the results have been speedy and dramatic. Though their eyesight will never be perfect, they are thrilled that for the first time in their lives they can see such wonders as stars in the night sky.

Part of the excitement of RPE65 gene therapy for researchers at the Save Sight Institute is that it might be the first, but it certainly won't be the only. "There are other companies with other medications and genetic therapies coming through," Robyn says. "They contact us all the time to ask if we have patients with particular gene issues, and would we be open to doing clinical trials with them. There's a real sense of excitement out there, particularly in the eye field, because people are getting genetic answers that lead to genetic therapies."

That said, and for reasons that aren't clear, gene therapies don't work for all people. There are times when the immune system attacks the neutralised virus, but other failures have no obvious explanation, so there's still a lot of work to be done.

"We now have more genetic answers for more people," Robyn says. "Our lab has identified novel disease genes and therapy approaches, and we've looked at what's been found internationally. We're looking for as many genetic answers and therapies for as many patients as we can."

As the work continues, the Save Sight Institute is preparing for possibly its biggest change since it was established as a Foundation of the University of Sydney in 1985. From 2028, it will have access to the new Sydney Biomedical Accelerator (SBA) ecosystem - a partnership between the University of Sydney, Sydney Local Health District and the NSW Government.

Central to this initiative is a new research complex that will span the University's Camperdown Campus and the District's Royal Prince Alfred Hospital campus, with the aim of supporting innovative research and fast-tracking scientific discovery. Researchers will share facilities with scientists with other biomedical skill sets, including biomedical engineers, bioinformatics experts and microscopy specialists, among others. The SBA will also enable easier access to resources and technologies that might now be spread less conveniently across the University's campuses.

"Research is now a team sport," Peter reflects. "For Save Sight Institute researchers, if they have a problem that's outside their field, chances are there'll be someone in the SBA who can help them solve it - or, even better, someone with another idea completely for advancing the work."

Peter hopes that the SBA will facilitate the development of therapies for currently untreatable blinding eye diseases, slow the onset of age-related eye disease, and lead to the development of a collaborative, national network of eye research institutes.

"It'll be a place where collaborations and relationships can grow from something as simple as a conversation in the lunchroom," he says. "As the name says, it will accelerate progress across a number of fields, making so much more possible."

Turning back the clock

The Save Sight Institute is tackling some of the biggest vision-related issues facing the world today.

One of the most common causes of irreversible blindness is glaucoma, which affects around 80 million people worldwide. The risk of developing glaucoma only increases with age and family history.

Ophthalmologist Professor Jonathan Crowston is working on ways to increase resilience in the optic nerve in order to slow or even stop the loss of vision caused by glaucoma. He has had some recent success with a pilot study into the use of vitamin B3 in treating people with glaucoma. The study showed positive short-term visual improvement in participants, and has now been expanded into four large studies involving more than 1,500 participants.

But Jonathan's long-term goal isn't just reducing the impacts of glaucoma. He wants to unpack the condition even further, to understand how ageing makes the optic nerve more vulnerable to injury and degeneration. Early studies have shown that simple lifestyle and pharmacological interventions can help to slow the biological hallmarks of ageing.

"We can potentially render nerves resistant to glaucoma," he says. "These therapies could boost nerve resilience to the point where they're effectively turning back the clock."