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Sydney surgeon details first Luxturna gene therapy allowing patient to see stars

The vitreoretinal surgeon who performed Australia’s first Luxturna gene therapy has described the intricacy of the procedure, while hailing the team effort that has resulted in profound vision improvements for patients, including one who reported seeing stars for the first time.

Rylee Jebara, 17, and 15-year-old brother Saman, both diagnosed with Leber congenital amaurosis in the first year of life, were the first Australians to receive Luxturna. The drug is the world’s first approved gene replacement therapy for an inherited blinding eye condition and one of the first gene replacements for any human disease.

A/Prof Matthew Simunovic.

Approved by the Therapeutic Goods Administration in August 2020, it is also the country’s first ‘in-vivo’ gene therapy, meaning it directly infects cells in the body. Luxturna treats children and adults with rare biallelic pathological mutations in RPE65.

Associate Professor Matthew Simunovic, vitreoretinal surgeon at the Sydney Eye Hospital and Sydney Children’s Hospitals Network (SCHN) and Associate Professor at the Save Sight Institute (SSI), performed the first surgery on Rylee via a subretinal injection.

He said it was an incredibly delicate procedure, with some eligible patients having paper- thin retinas. To be approved to perform the surgery, he received hands-on training in the surgical methods used in the development of Luxturna. One of his research interests is subretinal drug delivery and he used a modified version of a technique developed by a colleague in Oxford, UK.

“The delivery of Luxturna into the correct surgical plane is the crucial part of the procedure,” he said.

“It is injected via a 38-gauge Teflon-tipped cannula that punctures the retina, which is typically thinned in this group of patients. A further difficulty is the subretinal space is a ‘potential space’: that is, it needs to be defined. If you go too deep, you risk sub-retinal haemorrhage, retinal pigment epithelial (RPE) damage and loss of treatment effect. If too shallow, the drug will end up in the vitreous cavity, with a loss of treatment effect and the potential for intraocular inflammation.”

Simunovic performed the injection in two steps. First, he defined the surgical plane with an inert ‘balanced salt solution’, controlled using the foot pedal on a vitrectomy machine. On-table OCT then confirmed the solution was in the correct plane. The second step involved injecting 0.3mL of Luxturna into this sub-retinal bleb via the same puncture site; with the injection pressure controlled by the assisting vitreoretinal surgeon, Dr Gaurav Bhardwaj.

“This requires clear communication and teamwork – the trick is to deliver the treatment slowly, watching for retinal stretch, which can lead to iatrogenic macula hole formation,” Simunovic added.

Simunovic is part of Ocular Gene and Cell Therapies Australia (OGCTA), a new Sydney-based collaborative to accelerate the development of novel genetic therapies and offer genomic diagnosis for patients who may benefit from Luxturna and investigational therapies. It brings together experts in ocular genomics, functional investigations, investigation of novel ocular genetic and stem cell therapies, drug delivery and clinical expertise in genomic and ophthalmic diagnoses.

It involves the Genetic Eye Clinic at SCHN, the Eye Genetics Research Unit and Stem Cell Medicine Group at the Children’s Medical Research Institute (CMRI), and SSI at Sydney Eye Hospital and University of Sydney.

The Sydney team has now treated four people with Luxturna, including two adults in their 40s. For patients to ultimately receive Luxturna, Simunovic said it involved a significant team effort, including identifying suitable patients and ordering the medication with a minimum 12-month lead time, through to surgery planning and follow-up. Suitable patients must also have proven mutations to both of their RPE65 genes – responsible for recycling vitamin A in the retina – and deemed likely to benefit from treatment through testing.

“Generally, a treatment effect is noticed one month following treatment,” he said.

“Improvements following Luxturna gene therapy are probably best quantified by full-field stimulus testing (FST). The improvements correspond to – on average – a 100-fold improvement in sensitivity. This translates to improved function in real life. For example, Rylee stopped using a cane to navigate by streetlight about a month following treatment. When we caught up [recently], Rylee also reported having seen stars for the first time.”

A momentous milestone 

OGCTA lead Professor Robyn Jamieson – also head of the Eye Genetics Research Unit at SCHN and CMRI, and head of Specialty of Genomic Medicine at the University of Sydney – said it was remarkable to now see gene therapies used in the real world: “When I started in the field 20 years ago, we couldn’t even offer these people a hint of a genetic diagnosis.”

Robyn Jamieson_2020
Prof Robyn Jamieson.

She said the OGCTA builds on decades of work in Sydney, with one of its important functions bringing together a multi-disciplinary panel of expert ophthalmologists, geneticists, genetic counsellors and researchers who can determine eligible Luxturna recipients, as well as other diagnoses.

In some cases, patients may have a “variant of uncertain significance” – meaning the case is not clear cut. Here, the OGCTA can perform functional genomics where a blood sample is taken from the patient and grown into retinal organoids or RPE where researchers can then assess the mutation more closely and hopefully determine a diagnosis and eligibility for approved and/or pre-clinical treatments.

If confirmed to have the mutation, she said they need viable photoreceptor cells to clear the next hurdle towards treatment. This is where her husband and genetic eye disease expert Professor John Grigg, also part of OGCTA, performs retinal testing to determine if the patient will benefit.

The OGCTA’s activities also include developing gene and stem cell therapies, and clinical trials, with a focus on diseases groups like retinitis pigmentosa, cone-rod dystrophy and Usher syndrome. For Stargardt disease – a gene too large for viral vectors – the OGCTA is conducting trials for an oral therapy that works at the enzyme level, and is also looking at potential gene editing techniques.

More reading

Siblings treated with Luxturna gene therapy in Australian first (video included)

TGA approves Luxturna gene therapy

Tasmanian centre joins race for CRISPR blindness cures

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