Two siblings from Sydney, successfully treated with a novel ocular gene therapy for Leber congenital amaurosis (LCA), bring significant hope to 15,000 Australians who live with inherited retinal diseases, ophthalmologists say.
The ocular gene therapy, known as Luxturna and distributed in Australia by Novartis, has been approved by the Therapeutic Goods Administration to treat children and adults with biallelic pathological mutations in RPE65. Those born with this rare mutation in both copies of the RPE65 gene, believed to account for about 5-6% of all people with LCA, can suffer from a range of symptoms, including night blindness (nyctalopia), loss of light sensitivity, loss of peripheral vision, loss of sharpness or clarity of vision, and potentially, total blindness.
Successfully delivering the first approved gene therapy has been a fantastic team effort, and it underscores Australia’s capability in this field
The Australian-first surgeries, on 17-year-old Rylee and 15-year-old Saman in late 2020 and early 2021, were performed in Sydney by vitreoretinal surgeons Associate Professor Matthew Simunovic and Dr Gaurav Bhardwaj. The siblings, who were both diagnosed with LCA in their first year of life, experienced “profound” vision improvement immediately after their surgery.
Assoc/Prof Simunovic explained that the ocular gene therapy uses an adeno-associated virus as the vector to deliver the ‘correct’ copy of the RPE65 gene to retinal cells, where it replaces the faulty one.
“Because these cells don’t divide – and because of the ability of adeno-associated virus to produce long-term expression of protein, the effects are sustained in the treated retinal region,” he said.
A TECHNICALLY CHALLENGING PROCEDURE
The technically challenging procedure involves injecting the gene therapy via a 38-gauge Teflon-tipped cannula, held by the surgeon. The cannula punctures the retina, which is typically thinned in patients with LCA, and in some cases, can be as thin as a sheet of copy paper.
“A further difficulty is that the sub-retinal space is a ‘potential space’; that is, it needs to be defined,” he said. “If you go in too deep, you risk sub-retinal haemorrhage, retinal pigment epithelial damage and loss of treatment effect. If you are too shallow, the drug will end up in the vitreous cavity, with a loss of treatment effect and the potential for intraocular inflammation.”
Assoc/Prof Simunovic said Rylee and Saman’s profound improvements in their vision mirror results seen in the pivotal clinical trials.
“Importantly, such benefits appear to be sustained for many years – in fact, for as long as patients have been followed up. Successfully delivering the first approved gene therapy has been a fantastic team effort, and it underscores Australia’s capability in this field,” he added.
The therapy was delivered as part of Ocular Gene and Cell Therapies Australia (OGCTA), a new collaboration involving the Genetic Eye Clinic at Sydney Children’s Hospitals Network (SCHN), the Eye Genetics Research Unit and Stem Cell Medicine Group at the Children’s Medical Research Institute (CMRI), and the Save Sight Institute at Sydney Eye Hospital and University of Sydney.
CMRI was represented on this project by Professor Frank Martin, CMRI’s Board President; Professor Robyn Jamieson, Head of the Eye Genetics Research Unit at CMRI and SCHN; and Dr Anai Gonzalez Cordero, Head of the Stem Cell Medicine Group.
Professor Jamieson, who is also lead of OGCTA and Head, Specialty of Genomic Medicine, University of Sydney, said the “revolutionary” therapy would lead to transformation of care for patients with blinding eye diseases.
“Inherited retinal disease is a devastating diagnosis. Up until now, these patients suffered progressive vision loss that led to blindness and there was no therapy for them at all,” Professor Jamieson said.
“But through new genomic diagnostics, and the use of ocular gene therapy, we are finding that we have the ability to not only stop this ongoing progression but also help to improve vision for people who have RPE65-related retinal vision loss.”
“The real-world improvements in visual function have been quite remarkable, bringing to life the rather dry clinical trials outcome measures. It is tremendously heartening to see the changes in vision capabilities for these first patients treated with Luxturna,” said Professor John Grigg, Head of Specialty of Ophthalmology, Save Sight Institute, University of Sydney and lead inherited retinal disease specialist in OGTCA.
“As an ophthalmologist who has been caring for patients with Leber’s amaurosis for many years and unable to offer any treatment, it is incredibly rewarding to now have the opportunity to not only give families hope but also be involved in improving their child’s vision,” said Frank Martin, Clinical Professor in the Specialties of Paediatrics and Child Health and Ophthalmology at the University of Sydney.
Four patients in Australia with LCA have now been treated with Luxturna and while it can only be used to treat this specific form of the retinal disease, it does provide significant hope that similar treatments may be applied to other retinal disease genes in the future.
“This treatment establishes gene therapy as a proven treatment. That is, we have gone far beyond the proof-of-concept stage to establish efficacy, not only in Phase III studies, but increasingly in real-life, ‘Phase IV’ studies, which will be tracked internationally through ongoing collaborative efforts,” Assoc/Prof Simunovic said.
Professor Grigg concluded, “This heralds a new era in transforming the lives of these people who otherwise have a life of blindness ahead of them, and provides hope for more than 15,000 other affected Australians who live with some form of inherited retinal disease”.