WRITER Melanie Kell

In Search of Cures for Macular Disease

Since 2011, Macular Disease Foundation Australia (MDFA) has committed more than AU$6.9 million to world-leading Australian researchers with an aim to reduce the impact of macular and retinal diseases, find new treatments, and ultimately if possible, cures. Within a competitive landscape, this independent funding is invaluable as it enables research to be pursued without constraint. This article explores the ongoing work of four researchers currently funded by MDFA research grants: Dr Jiang-Hui (Sloan) Wang, Professor Mark Gillies, Dr Sushma Anand, and Professor Erica Fletcher.

Dr Jiang-Hui (Sloan) Wang, an early-career scientist and head of newly established Ocular Genetic Therapeutics Unit at the Centre for Eye Research Australia (CERA), is working to solve one of gene therapy’s most stubborn engineering problems. In doing so, he may open the door to treatments for a range of inherited retinal diseases.

For the estimated one in 8,000 to 10,000 people living with Stargardt disease, the progressive loss of central vision has long come without the prospect of a meaningful treatment. That picture, however, is beginning to change because Dr Wang is developing a next-generation gene therapy approach that could not only transform care for Stargardt patients, but reshape what is possible across a broader spectrum of inherited retinal diseases.

The project, supported by a Grant Family Fund award from MDFA, centres on delivering a functional copy of the ABCA4 gene – the faulty gene at the root of Stargardt disease – directly into photoreceptors using a specially engineered viral vector. The challenge, as Dr Wang explained, is considerably more complex than it might first appear.

“ABCA4 is a particularly challenging gene to deliver because it is large – larger than what a standard AAV vector can comfortably package as a single, intact gene,” he said. “In Stargardt disease, ABCA4 normally helps photoreceptors clear toxic by-products of the visual cycle. When ABCA4 is faulty, these by-products accumulate and contribute to retinal damage, particularly in the macula.”

A TWOFOLD ENGINEERING CHALLENGE

Dr Wang, who trained under gene therapy pioneer Professor Guangping Gao at the University of Massachusetts Chan Medical School, described the core problem as twofold. “The key challenge is: first, delivering a full, functional ABCA4 payload safely; and second, getting that payload into the right retinal cells efficiently and durably via a safer, less invasive administration routeintravitreal injection,” he explained. “Our approach tackles both.”

His 1A solution draws on an engineered viral capsid he developed during his time in the United States, which has since been validated in both small and large animal models. Working in parallel, his team is optimising gene delivery designs so that the full-length therapeutic ABCA4 gene can be expressed robustly and sustainably once inside the target photoreceptors. The ultimate aim, he said, is straightforward: restore the cell’s ability to do what it was always supposed to do.

“At the photoreceptor level, the goal is to restore ABCA4 activity so photoreceptors can again process and clear retinal metabolic by-products that otherwise accumulate and contribute to degeneration,” Dr Wang said. “If we can reintroduce functional ABCA4 and achieve sufficient expression in the right cells, we expect to reduce the build-up of toxic compounds, preserve photoreceptor health, and ultimately help stabilise, or potentially improve, visual function over time.”

TESTING IN MOUSE MODELS

To demonstrate that the therapy works in practice, Dr Wang’s team will test the approach in mouse models of Stargardt disease using a combination of structural, functional, and molecular readouts. These will include retinal imaging and histology to evaluate photoreceptor integrity over time, electrophysiological and visual function testing to quantify improvements in treated eyes, and confirmation of therapeutic gene expression and distribution across the retina.

“Using these endpoints together helps us demonstrate not only that the gene is delivered, but that it produces meaningful biological and functional benefit,” he said.

WHAT CLINICIANS SHOULD KNOW

For optometrists and ophthalmologists managing Stargardt patients today, Dr Wang offered guidance on how to frame conversations about gene therapy. Patient selection, he explained, would likely prioritise individuals with a genetically confirmed ABCA4-associated diagnosis and evidence of viable photoreceptors remaining in the target retinal regions – because gene therapy requires living cells to rescue.

“In general, earlier-stage disease, where more retinal cells remain, is more likely to benefit,” he said, adding that exact criteria would depend on the final clinical trial design. On counselling patients about timelines and expectations, he said that although gene therapy development is progressing quickly, moving from preclinical work to human trials still requires time for manufacturing, safety studies, and regulatory review. Early trials, he noted, would primarily assess safety and dosing, with benefits potentially measured initially as slowed progression rather than dramatic vision restoration.

“The most helpful message is that gene therapy is becoming increasingly feasible for Stargardt disease, but it is not yet ‘one-sizefits-all’, and outcomes will depend on disease stage and retinal cell survival,” he said. He also recommended that eye care professionals continue with regular imaging and functional assessments of Stargardt patients, noting that these data will be essential for determining eligibility and tracking outcomes once trials become available.

A PLATFORM FOR BROADER IMPACT

Perhaps most exciting for the broader field is the potential reach of the platform Dr Wang is building. Many inherited retinal diseases involve genes too large for conventional AAV delivery – a bottleneck that has long frustrated clinical translation. Dr Wang believes the enhanced delivery framework he has developed for Stargardt disease could be adapted for conditions such as Usher syndrome and other retinal dystrophies.

“For conditions such as Usher syndrome and other retinal dystrophies, the same principles apply: deliver the therapeutic gene to the appropriate retinal cell type with enough efficiency and durability to change disease trajectory, while maintaining safety,” he explained. “If we can establish a reliable ‘playbook’ for enhanced retinal AAV delivery, it could accelerate development across a range of inherited retinal diseases – particularly those that have been harder to treat due to payload size constraints and delivery barriers.”

Anti-VEGF therapy has transformed the management of neovascular age-related macular degeneration (nAMD) – but for many patients, the battle is far from over.

Professor Mark Gillies – Director of Research at the Save Sight Institute, University of Sydney, and Head of the Medical Retina Clinic at Sydney Eye Hospital – is working to better understand, and ultimately prevent, the end-stage complications that continue to steal vision, even in treated eyes.

When anti-VEGF injections arrived, they changed everything. For the first time, clinicians had a powerful tool to suppress the abnormal blood vessel growth driving neovascular AMD (nAMD), and vision that would once have been lost could be preserved. Yet decades on from those early trials – trials in which Prof Gillies himself played a central role – a troubling reality persists: roughly half of all patients treated with anti-VEGF therapy will go on to develop macular atrophy or subretinal fibrosis, both of which cause irreversible vision loss.

NOT A PARADOX, BUT A PROGRESSION

It might seem contradictory that patients whose nAMD is being successfully controlled continue to lose vision to atrophy and fibrosis, however Prof Gillies takes a different perspective. “It is not really a paradox,” he explained. “Eyes that develop neovascular AMD have more advanced disease, and eyes with more advanced disease also tend to develop atrophy. AMD is a condition that continues to advance towards macular atrophy, irrespective of whether eyes develop bleeding and it is successfully treated or not, if a patient lives long enough.”

The question of whether anti-VEGF therapy itself accelerates atrophy has attracted considerable debate. “It has been speculated that VEGF inhibitors may hasten the development of atrophy,” Prof Gillies said, “but it is also very likely to have occurred anyway in these eyes.

“Even if VEGF inhibitors do exacerbate atrophy, stopping treatment or even relaxing it risks much more rapid vision loss through reactivation of the neovascularisation.”

WHAT THE REAL-WORLD DATA REVEALS

Prof Gillies is the Australian ophthalmologist and researcher who initiated the Fight Retinal Blindness! (FRB!) project, one of the world’s most advanced internet-based platforms for tracking real-world outcomes of eye injection treatments. This extraordinary platform has generated evidence about why patients so often fail to maintain their early vision gains – and it’s from here that Prof Gillies gains insights that can differ from the findings of randomised clinical trials (RCTs).

“We have very good data that VEGF inhibitors are highly effective for neovascular AMD,” he said, “and have produced evidence that the main problem is that patients are undertreated. We’ve also demonstrated that the reason patients do not maintain their initial vision gains after starting VEGF inhibitors is mostly because they develop either atrophy or retinal fibrosis.”

He said results from RCTs “are generally much better than in real-world practice for a number of reasons” because “they exclude many patients that we still need to deal with, such as those with very good or very poor vision, and those with poor health”.

“Randomised trials also push patients with incentives and subsidies to attend visits, which does not happen in routine clinical practice.”

Conversely, he said, real-world registries like FRB! capture the full complexity of the patients that clinicians encounter every day.

His team is now developing a module for intermediate AMD within the platform that Prof Gillies hopes may answer important questions about which patients are at greatest risk of progressing before end-stage complications emerge.

WHAT CLINICIANS SHOULD WATCH FOR

For optometrists and ophthalmologists monitoring patients being treated with anti-VEGF therapy, Prof Gillies said specific optical coherence tomography (OCT) findings demand attention. “The signs that precede retinal fibrosis – mainly subretinal hyperreflective material (SHRM) and bleeding – are fairly well understood,” he said. “They need to be recognised early and should be treated more aggressively to resolve them before they turn into a scar.

“On the question of atrophy, we can slow down its expansion sometimes with the new complement inhibitors, but there may be more we can do to delay its appearance in the first place.”

However, his team is doing its best to better understand the pathway. One project underway is to analyse “whether tolerating a certain amount of retinal swelling, particularly if it is confined to just beneath the retina rather than in the retina, may slow progression of atrophy”. The findings could have practical implications for how treat-and-extend protocols are individualised.

Another project – also funded by MDFA – is testing whether lower rates of atrophy are associated with any of the currently available VEGF inhibitors, of which there are around six, all acting in subtly different ways that may be beneficial beyond simply stopping the bleeding.

Yet another project is exploring the metabolism underlying macular telangietasia type two (MacTel), in which low serine levels drive the accumulation of toxic deoxysphingolipids, causing damage to the macula. “We do know that the macula has one of the highest metabolic rates in the body so interventions to improve macular metabolism, one of which is photobiomodulation (red light therapy), may slow the degenerative process and thereby reduce the risk of eyes with intermediate macular degeneration progressing to the advanced form,” he explained.

For subretinal fibrosis, however, the emphasis remains on prevention. “Subretinal fibrosis is generally due to undertreatment,” Prof Gillies said. “Recognising the signs that precede it and treating more aggressively when they are developing is the key.”

Dr Sushma Anand, a postdoctoral fellow at Centre for Eye Research Australia, is harnessing the body’s own biological machinery to deliver medicines directly to the retinal cells that need them most.

Treatment options for patients living with Stargardt disease and MacTel remain frustratingly limited. Both conditions cause progressive, irreversible vision loss, and currently there is no cure, something that Dr Anand is determined to change.

With the support of a MDFA Grant Family Fund award, she is developing an exosome-based therapeutic delivery platform designed to target the underlying mechanisms of both conditions.

Dr Anand’s approach is as elegant as it is innovative. Instead of relying on synthetic or viral carriers to transport medicines into the eye, she is using exosomes – tiny, naturally occurring vesicles produced by cells – to deliver therapeutic cargo with precision while minimising risk to the patient.

WHY EXOSOMES MATTER

Exosomes are nanoscale particles released by virtually all cell types, serving as natural messengers that shuttle proteins, lipids, and genetic material between cells. Because they originate from the body itself, they are inherently compatible with human biology – a property that Dr Anand believes gives them a significant edge over existing delivery technologies.

“Exosomes are natural, cell-derived vesicles that can deliver therapeutic cargo directly to retinal cells, making them uniquely suited for targeted therapy,” she explained. “Unlike conventional viral vectors such as AAV, exosomes are non-immunogenic, highly biocompatible, and capable of carrying a wide range of therapeutic molecules, including genes, proteins, or small metabolites.”

This versatility is particularly important when treating the eye, where immune responses and off-target effects can be difficult to manage.

ONE PLATFORM, TWO DISTINCT CONDITIONS

Dr Anand’s project targets Stargardt disease and MacTel using two different but complementary exosome-based strategies.

Stargardt disease is caused by mutations in the ABCA4 gene, which encodes a protein essential to the visual cycle. And as Dr Wang explained earlier in this article, a key challenge in treating the condition with conventional gene therapy is that the ABCA4 gene is too large to fit within standard adenoassociated virus (AAV) vectors.

Dr Anand said exosomes offer a solution to this longstanding obstacle.

“Exosomes offer a powerful platform for precision medicine in the retina, reducing off-target effects and increasing therapeutic effectiveness, potentially overcoming limitations of current approaches.”

For MacTel, the challenge is metabolic rather than genetic. As Prof Gillies pointed out, patients with MacTel have low levels of serine, an amino acid critical to the health of retinal Müller glia and photoreceptors. Dr Anand’s team is working to package serine into exosomes and deliver it directly to the retinal cells where it is needed most, aiming to restore metabolic balance and protect vision.

“We have already generated promising preliminary data showing successful packaging of serine into exosomes,” she said, “while in parallel we are optimising plasmid packing to enable gene delivery directly to retinal cells.”

WHERE THE RESEARCH STANDS

Dr Anand’s platform is currently at the preclinical stage. Once packaging and delivery protocols have been validated in cell models, her team will progress to evaluating safety and efficacy in disease models – a necessary step before any regulatory pathway toward clinical trials can begin.

Although the journey to clinical application will take several years, she said “our goal is to develop treatments that are safe, precise, and effective, targeting the underlying disease mechanisms rather than just managing symptoms”.

A PLATFORM WITH BROADER HORIZONS

Beyond Stargardt disease and MacTel, Dr Anand said the platform’s potential has far-reaching potential. Exosome-mediated delivery could eventually be adapted for other retinal conditions including AMD, diabetic retinopathy, and glaucoma, where localised delivery of therapeutic molecules could help prevent cell loss and preserve vision.

“Because exosomes can carry diverse cargo and be engineered to target specific cell types, they offer exciting possibilities, from supplementing deficient enzymes and delivering gene therapies to modulating inflammation in the retina,” she said. “This versatility positions exosomes as a potentially transformative tool in ophthalmology.”

Erica Fletcher, a Professor in the Department of Anatomy and Physiology at the University of Melbourne, is using patients’ own blood cells to investigate why some people with AMD progress faster than others – and to find the compounds that might one day stop it.

For the millions of Australians living with AMD, the path from early diagnosis to late-stage vision loss remains frustratingly difficult to predict – and even harder to prevent. Prof Fletcher and her team aim to change that by homing in on a neglected player in the disease process: the retina’s own immune cells.

Prof Fletcher has spent more than two decades studying retinal diseases. With support from a MDFA research grant, she and her team are now focusing on reticular pseudodrusen (RPD) – a specific type of waste deposit that forms within the retina and is strongly associated with rapid progression to late-stage AMD.

A HIGH-RISK SIGN

Reticular pseudodrusen represent a high-risk sign for AMD progression, particularly to geographic atrophy. One 2024 study showed that patients presenting with large drusen greater than 125 micrometres, combined with pigmentary changes in both eyes and the presence of reticular pseudodrusen, faced a 73% risk of progression over five years.1

“This new ‘risk algorithm’ highlights that looking for reticular pseudodrusen in our patients is important for identifying those who need to be more carefully managed,” said Prof Fletcher.

Unlike drusen, which form beneath the retinal pigment epithelium, RPD deposits form within the retina itself – a distinction that is central to Prof Fletcher’s hypothesis about the immune cells responsible for clearing retinal waste.

GROWING PATIENTS’ IMMUNE CELLS IN A DISH

At the centre of Prof Fletcher’s research are microglia – the resident immune cells of the retina and brain responsible for clearing the waste that naturally accumulates with age. Her team’s central question is whether these cells are functionally impaired in people who develop reticular pseudodrusen, and whether that impairment could explain why certain patients deteriorate more rapidly.

To answer this, the team is using a novel approach: generating microglia directly from patients’ blood samples. Three groups are represented – people with AMD who have reticular pseudodrusen, people with AMD who do not have reticular pseudodrusen, and healthy controls without AMD. By cultivating these cells in the laboratory, the researchers can compare their waste removal capacity across groups and correlate findings with each individual’s genetic profile.

Prof Fletcher said this personalised model will enable her team to directly identify whether cells are abnormal in people with reticular pseudodrusen and compare the function of those cells with an individual’s genetics. This information could be important for generating new therapies that target microglial function.

By working with living cells derived from the very patients under study – rather than animal tissue or post-mortem samples – her team can observe how AMD-associated biology plays out in real time – and in a system that reflects genuine human genetic diversity.

SCREENING 3,000 COMPOUNDS FOR NEW TREATMENTS

Beyond characterising microglial dysfunction, Prof Fletcher’s team is using these patient-derived cells as a platform for drug discovery. Using an automated approach, they will screen approximately 3,000 compounds for their capacity to enhance waste removal in microglia, to identify those with the highest therapeutic potential.

Once the most promising candidates have been identified, the team will need to determine the best delivery mechanism and confirm efficacy in living patients. While this entire process could take years, Prof Fletcher said “screening compounds that enhance waste removal is the first step in the development of new therapies that target microglia”.

TOWARDS PERSONALISED PREVENTION

Perhaps the most transformative implication of Prof Fletcher’s work lies not simply in finding new drugs, but in reshaping the entire clinical approach to AMD management. If microglial function can be tested from a blood sample, it may one day be possible to tailor treatment to an individual patient’s biology – intervening before disease progresses to an advanced stage.

Prof Fletcher described a future scenario in which a patient found to have reticular pseudodrusen could have their microglia tested in a laboratory dish for functional abnormalities, and then potentially be treated before their RPD had progressed to advanced AMD. By taking a sample of blood cells, she said, it may become possible to tailor individual therapies to the functional changes in microglia.

Reference available at mivision.com.au.

All four researchers expressed their appreciation for the funding received from MDFA. At a time when competitive government grants have become increasingly difficult to secure, Prof Fletcher said MDFA funding had been critical, and that without it her team would not be able to generate microglia from patient samples nor test the compound library.

Prof Gillies said the independent funding from the MDFA had been invaluable to his research and particularly the Fight Retinal Blindness! project.

“We tend to rely on drug companies,” he explained, “but it is possible that we lose a certain amount of independence from this, although we do as much as we can to minimise this. The MDFA places no constraints on our research.

“The FRB! platform also cannot charge the practitioners who contribute data – to do so would reduce the volume and breadth of information the project receives.”

For Dr Anand, seed funding was instrumental in enabling her early-stage work, which didn’t have the evidence base needed to attract larger grants. And the support she received did more than simply pay for equipment and personnel.

“MDFA funding provides assurance that the project has been reviewed and endorsed by community members who understand the importance of these preclinical studies,” she explained. “This community confidence is critical for attracting additional support and moving toward clinical trials.”