Australians at the cutting-edge of gene therapy research


From the beginning of the genetic revolution when the double helix DNA model was first described in the 1950s, to recoding our genetic makeup, medicine has taken strides that were once unfathomable by treating disease at the crux – and ophthalmology is at the forefront.

Globally, medicine is transitioning towards genetically tailored therapeutic options. Gene therapy interventions have exploded on to the clinical landscape with its potential to treat disease on the genome level.

This radical shift has seen rapid market expansion, with Australia welcoming its first approved ophthalmic gene therapy, Luxturna, in 2020 and an unprecedented number of programs entering clinical trial stages here and abroad.

Insight provides a snapshot of the Australian gene therapy landscape and shines a light on the current research focus in this space and its projection.

One size fits all

Although the current pipeline is robust, and advancing rapidly, many of the therapies are highly targeted for rare genetic diseases, culminating in multiple programs that stand to benefit a small proportion of patients.

Associate Professor at the University of Melbourne and Centre for Eye Research Australia (CERA), Dr Lauren Ayton, believes the infrequency of these genetic mutations among patient cohorts means the future of gene therapy will see a shift from specific, highly targeted therapies, to broad spectrum genetic approaches.

With its large socio-economic impact, Dr Ayton has dedicated her work to therapeutic interventions in this space with a particular focus on inherited retinal diseases (IRDs). This refers to 300 different known genes that can cause degenerative eye disease, which collectively are the most common cause of blindness in working-aged Australians.

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Dr Lauren Ayton and the VENTURE team at CERA. Image: Image: Anna Carlile/CERA.

At CERA, Dr Ayton says it begins with identifying candidates for gene therapy through genetic screening.

Her group has a natural history registry called VENTURE which involves enrolling people with an IRD with the goal of learning more about these conditions in preparation for the oncoming stream of gene therapies. The team collects clinical data on their disease pathophysiology and offers them genetic testing where possible.

The clinical trials are a collaboration between CERA, the University of Melbourne, and the Royal Victorian Eye and Ear Hospital.

“We almost see it as our central research pillar,” Dr Ayton says, noting the VENTURE program facilitates gene therapy research by collecting patient samples and generating stem cells to learn more about disease. “It’s like an ecosystem of research into IRD, allowing us to learn more about the disease process, but also how the conditions impact on people’s quality-of-life.”

IRDs are a target for current gene therapies due to their monogeneity. That is, there is a single defective gene.

In this space, Dr Ayton says the future lies in “non-specific” drug gene therapy targets. Currently, the number of genes implicated in IRDs creates a burden of tailoring therapies to each defective gene.

“There are over 300 genes that are known to cause IRD, so it’s a really long pipeline if we’re going to try and correct every single one individually. We’re not going to be able to do this, because some of these genes are too big to fit into a normal vector for gene therapy,” Dr Ayton says.

Genetic heterogeneity – when different genetic defects cause the same disease – is a significant limitation in gene therapy development. As there are so many potential target genes, the costs of developing individualised therapies are excessive. Gene-agnostic therapeutic approaches target pathways, as opposed to genetic factors, are thereby broadening the benefits to a larger cohort of IRD patients.

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1.CVS Health Gene Therapy Report Q1 2024 – Q4 2026.

“What I’m most excited about is what we call the gene-agnostic treatments. That involves using gene therapy or potentially stem cells to treat patients, no matter what their gene is,” Dr Ayton says.

“That’s what I’m looking forward to: being able to offer these treatments to everyone, rather than just a smaller cohort.”

Gene therapy delivery methods include traditional mechanisms such as viral vectors, the most common of these being the adeno-associated virus (AVV). Dr Ayton says this has now extended to novel methods, including nanoparticles of metal such as gold, and liposomes.

“We don’t know what is going to be best for patients now. So, I think it’s important that we keep supporting the different therapies that are out there. It’s a very exciting time for people with IRDs, who have not had the opportunity to access treatments before,” Dr Ayton says. “But we do need to temper the excitement with knowledge of the significant challenges that the research field faces.”

One such barrier in gene therapy trial programs is the small sample sizes available to researchers. This is due to the rarity of IRDs, but to compensate for this – and amass a larger patient cohort – CERA is part of an international consortium called the Foundation for Fighting Blindness. Here, with informed patient consent, it shares data internationally to increase patient numbers for a particular disease subset.

For Dr Ayton, the future lies in advanced genetic testing to map out disease.

“We’re starting to get more involved in research into the genetics of these conditions, led in large part by my colleague Dr Ceecee Britten-Jones and our colleagues at the Ocular Genetics Clinic, Royal Victorian Eye and Ear Hospital.

“We’re trying to learn more about the unknown. We’re hoping that learning more about the causes of these diseases will then lead to other opportunities for new treatments as well.”

Patients can be referred for the VENTURE registry at [email protected]

Switching it up

In the works at CERA is SwitchGene therapy for diabetic retinopathy. Led by Dr Ayton’s colleague, Associate Professor Guei-Sheung (Rick) Liu, SwitchGene has been in development for the last five years and is currently in the preclinical phase. The therapy uses a novel mechanism of action that selectively inhibits vascular endothelial growth factor (VEGF) in a controlled manner. This is opposed to continual suppression offered by conventional gene therapies.

Dr Rick Liu’s lab is working on SwitchGene therapy for diabetic retinopathy which selectively inhibits VEGF. Image: Image: Mathew Lynn/CERA.

Some diseases require lifetime treatment, but for other diseases constant activation of certain genes can be harmful. For example, indefinite activation of anti-angiogenesis genes can result in adverse effects such as hemorrhage, clots in the arteries (with resultant stroke or heart attack), hypertension, and impaired wound healing.

To circumvent this, SwitchGene involves a single intravitreal delivery of the necessary gene to the back of the eye. Then, the gene is activated when required through administration of eye drops.

“Conventional gene therapy continually neutralises VEGF, thereby significantly reducing VEGF in the back of the eye. This might have some negative effects and impact the normal capillary vessels in the retina,” Dr Liu says.

“We have to remember that VEGF is an important growth factor for maintaining vascular integrity and homeostasis in the retinal tissue as well. So, in the long term, this may also damage the retina.”

Relative to conventional gene therapies, Dr Liu says SwitchGene offers a potentially improved safety profile.

“Our idea was to create a gene therapy that was in control. We control when we need it activated and silenced,” he says.

The therapy could also work to alleviate some healthcare burdens, with the potential for patients to self-administer the drops without the need for a specialist.

“SwitchGene can save a lot of costs because you don’t need to administer intravitreal injections once a month as is the case with existing anti-VEGF therapies. The eye drops are also a cheap formulation so it would be affordable to patients.”

It is difficult for eye drops carrying larger drug molecules, such as anti-VEGF drugs, to penetrate the cornea for entry into the back of the eye. Therefore, existing anti-VEGF drugs require frequent intravitreal injections by a retinal specialist. Instead, Dr Liu’s team performs a single intravitreal injection that delivers the gene therapy into the back of the eye. The molecule used to activate the gene therapy – which is relatively smaller – is a good candidate for administration by eye drops.

Currently, the eye drops are effective for two days with Dr Liu hoping to extend the efficacy for up to a week.

To advance the therapy further, Dr Liu’s team want to titrate the therapeutic via the eye drops to suit the individual’s needs. Because everyone presents with different degrees of disease and progression, a dose that’s effective for one person won’t necessarily be effective for another.

“For example, when a patient goes to see an ophthalmologist, and they’re diagnosed with very early-stage disease, the surgeon can then recommend administration of a lower dose of eye drops after the gene therapy,” Dr Liu says. “And if a patient presents with more severe disease, we’ll recommend a higher dose to induce acute activation.”

Another promising development in gene therapy is the mRNA retinal delivery method. Dr Liu’s lab is also exploring the delivery of gene editing therapy in mRNA form for treating IRDs. This approach works by using mRNA to direct the retinal cells to make a gene editing protein using its natural machinery and correct the error genetic code.

Once its corrected, there is no need for further treatment intervention. Although this gene editing technology has entered clinical trials for metabolic disorders, delivery into the retina is a challenge.

Since gene editing therapy only requires transient expression of the editing machinery in the retina, an mRNA form of the treatment makes it a viable option.

“This way, you will carry the genetic correction your entire life. You won’t need to worry how long the treatment will last and what sort of side effects they may cause by the delivered gene,” Dr Liu says. 

“The disease is essentially being cured.”

The future is bright for RNA

Associate Professor Fred Chen, of Lions Eye Institute (LEI), is developing a precision RNA therapeutic for patients with IRDs.

He primarily works with antisense oligonucleotides, which are advantageous over traditional viral method delivery methods due to a lower chance of inducing an immune response.

Image: Fred Chen.

These molecules bind to RNA as opposed to DNA, reducing the risk of genotoxicity because the molecule can’t integrate into the genome.

He says that RNA precision therapy shines an optimistic light on the future of gene therapy.

“I think there’s a tremendous future in this approach because many mutations causing inherited retinal diseases affect how RNA molecules are processed. Since the molecule stays in the cells for a long time, retreatment can be given over several months if not years,” Dr Chen says.

“The other advantage of antisense oligonucleotides is that it can allow very fine tuning of the expression of the gene. Whereas with gene replacement therapy, we have no control over the dosage that each cell receives. The over production of certain proteins in the retina may also be detrimental.”

VP-001, an antisense oligonucleotide, has progressed to clinical trial stages and is a joint venture company between LEI and PYC Therapeutics. The therapy targets retinitis pigmentosa type 11, a monogenic, dominantly inherited, severe and progressive blinding disease.

“That product is now in Phase 1 trials in the US. Once these patients complete the trial, the FDA will examine the clinical and laboratory data to ensure that there are no safety concerns. If there are no issues, Phase 2 trial will commence shortly,” Dr Chen says.

He says regulatory hurdles are necessary to ensure safety for patients but this slows the approval process. Pre-clinical development through to market approval can take 10 to 15 years, which some of these patients do not have.

“As more of these gene therapies are commercialised and approved, the regulatory process for bringing these treatments to the clinic will become faster and easier.”

He adds: “The traditional model of doing large, randomised controlled trials is not feasible for a lot of these patients simply because there aren’t enough patients to participate in these trials. There’s a steep learning curve even within the regulatory agency for adopting a different approach to streamline the approval process of these personalised treatments.”

Dr Chen says the biggest hurdle his lab faces is predicting and measuring disease progression. Particularly for diseases that progress slowly over decades, clinical trials may have to be conducted over many years to demonstrate efficacy.

Traditionally, when therapies come to market, there is a post-marketing surveillance program to ensure the efficacy observed in clinical trials are also replicated in the real-world. This is a dynamic process whereby the treatment’s safety and efficacy are constantly being monitored.

Clear progression of Stargardt disease despite stability of visual acuity due to sparing of the fovea (centre point of the retina) by the atrophy (dark patches in the centre). Image: Fred Chen.

The aim of many of these therapies is to slow down or stop disease progression, which is difficult to quantify. The FDA usually wants to see improvements in visual acuity in ophthalmic clinical trials, which is not always a viable endpoint due to the nature of the diseases.

Dr Chen says that, as a result of the slow change in traditional endpoints such as visual acuity, there is an emphasis on implementation of surrogate biomarkers using high-resolution cellular imaging, which is a refined way to measure retinal cell integrity and ascertain the degree of disease progression in a matter of months as opposed to years. 

“For example, rather than looking at visual acuity, we can look at retinal thickness, atrophy area, number of cells and cell density, and the size of blind spots,” Dr Chen says.

“Despite visual acuity being the most commonly-adopted endpoint for any eye treatment, most inherited retinal diseases patients would tell me that their visual acuity has not changed in decades and so we really cannot use that parameter as a measure of successful treatment.”

Some gene therapies have failed to receive approval, despite demonstrating clinical efficacy, due to nonsensical endpoint criteria which are not suitable for diseases that progress over decades, Dr Chen says.

“With diseases that take decades to progress, it’s not feasible to use visual acuity as an endpoint.”

The devil’s in the genetic details

Professor John  Grigg is a clinical and experimental ophthalmology specialist at the University of Sydney and is a member of the Eye Genetics Research Unit led by Professor Robyn Jamieson at the Children’s Medical Research Institute and Save Sight Institute.

His principal role is in genotype-phenotype correlations, developing outcome measures for clinical trials and overseeing those clinical trials. He says this role is essential in mobilising the development of genetic therapies.

Additionally, Jamieson’s work – which highlights that clinical genetics underpins everything – determines whether gene replacement, editing or silencing is required.  In her role as head of the Eye Genetics Research Unit, Jamieson oversees the development of new therapies, investigating inconclusive genetic results and identifying patients for clinical trials.

A key figure in the Australian gene therapy landscape, Dr Grigg along with Jamieson, Professor Matthew Simunovic and Dr Gaurav Bhardwaj, were among the team to first deliver the Luxturna therapy; the first prescription gene therapy to help improve functional vision in patients with IRD.

Image: John Grigg.

Luxturna – a subretinal injection used to treat patients with IRD caused by RPE65 mutations and the first genetic therapy for inherited blinding eye conditions – gained FDA approval in 2017 and TGA approval in 2020. It effectively established the regulatory framework in Australia for future gene therapies to adhere to. Since its approval in Australia, 10 patients with mutations in RPE65 have been treated with Luxturna with another six patients being worked up for the therapy.

In the lead-up to its approval, a gene and cell therapy working group – Ocular Gene and Cell Therapies Australia (OGCTA) – comprising 16 primary members was established. The group brought clinical and molecular genetics together with ophthalmology, vitreoretinal surgery, orthoptics and nursing. The team ensured all the regulatory infrastructure was in place and that Luxturna complied with the gene regulatory agency.

“The OGCTA team, chaired by Jamieson, provides an excellent collaborative environment to bring together the clinical geneticists, molecular scientists and ophthalmologists to optimise the care for IRD patients. With Luxturna, we were paving the way, so that now means there’s a pathway established of how to do this in ocular gene therapies which makes it easier for everybody else to come through,” Dr Grigg says. 

Dr Grigg says a notable challenge in administering this therapy is health equity. He says that although specialised IRD ophthalmic and genetic services exist in each state, the funding models are outdated. Since IRDs are now the most common cause of blind registrations in Australia, Dr Grigg says the IRD workforce needs genetic counselling and orthoptic and ophthalmology enhancement to ensure affected individuals receive timely care.

“A federated disease registry process will ensure each state has their own disease registry that adheres to local governance systems and comes together to form a national dataset,” he says.

According to Dr Grigg, Australia boasts a good clinical trial and regulatory environment, which will hopefully attract the next generation of gene therapies. This provides hope to patients that they will receive the latest clinical care. 

More reading

Gene therapy could replace current nAMD treatments

Gene therapy trial for dry AMD under way in Australia

TGA approves Luxturna gene therapy


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