A pioneering genetic medicine has delivered life-changing improvements in sight to four children born with severe vision impairment from a rare genetic deficiency that affects the AIPL1 gene.
The condition, a form of retinal dystrophy, means those affected are born with only enough sight to distinguish between light and darkness. The gene defect causes the retinal cells to malfunction and die, with children affected being legally certified as blind from birth.
University College London Institute of Ophthalmology and Moorfields Eye Hospital, with the support of MeiraGTx.
The new treatment, developed by University College London Institute of Ophthalmology and Moorfields Eye Hospital, with the support of MeiraGTx, is designed to enable the retinal cells to work better and to survive longer, reports News-Medical.net.
The procedure, developed by UCL scientists, consists of injecting healthy copies of the gene into the retina, at the back of the eye through keyhole surgery. These copies are contained inside a harmless virus, so can penetrate the retinal cells and replace the defective gene.
The condition is very rare, and the first children identified were from overseas. To mitigate any potential safety issues, they received this novel therapy in one eye only. All four saw remarkable improvements in the treated eye over the next three to four years, but lost sight in their untreated eye.
The outcomes of the new treatment, reported in The Lancet, show that gene therapy at an early age can dramatically improve sight for children with this condition – one that is rare and particularly severe. Successful gene therapy for another form of genetic blindness (RPE65 deficiency) has been available on the NHS since 2020.
These new findings offer hope that children affected by both rare and more common forms of genetic blindness may, in time, also benefit from genetic medicine.
The team is now exploring the means to make this new treatment more widely available.
Professor James Bainbridge, professor of retinal studies at UCL Institute of Ophthalmology and consultant retinal surgeon at Moorfields Eye Hospital, said that sight impairment in children has a devastating effect on their development. “Treatment in infancy with this new genetic medicine can transform their lives.”
Professor Michel Michaelides, professor of ophthalmology at the UCL Institute of Ophthalmology and consultant retinal specialist at Moorfields Eye Hospital, said: “We have, for the first time, an effective treatment for the most severe form of childhood blindness, and a potential paradigm shift to treatment at the earliest stages of the disease. The outcomes for these children are hugely impressive and show the power of gene therapy to change lives.”
The treatment was developed and manufactured at UCL under a Manufacturer’s ‘Specials’ Licence (MSL) held by UCL. MeiraGTx supported production, storage, quality assurance and released and supplied it for treatment under the genetic medicine company’s MSL.
Study details
Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study
Prof Michel Michaelides, Yannik Laich, Sui Chien Wong, Ngozi Oluonye, Serena Zaman, Neruban Kumaran, et al.
Published in The Lancet on 22 February 2025
Summary
Background
Retinal dystrophy caused by genetic deficiency of AIPL1 causes severe and rapidly progressive impairment of sight from birth. We sought to evaluate whether early intervention by gene supplementation therapy was safe and could improve outcomes in children with this condition.
Methods
This non-randomised, single-arm, clinical study conducted in the UK involved four children aged 1·0–2·8 years with severe retinal dystrophy associated with biallelic disease-causing sequence variants in AIPL1. We designed a recombinant adeno-associated viral vector comprising the human AIPL1 coding sequence driven by a human rhodopsin kinase promoter region (rAAV8.hRKp.AIPL1). The product was manufactured under a Specials Licence from the Medicines and Health products Regulatory Authority (UK) and made available to affected children with local ethics approval. We administered the product to one eye of each child by subretinal injection. The children were prescribed oral prednisolone to protect against harm from inflammation. Outcome measures included visual acuity (as assessed with a novel touchscreen test), functional vision (assessed by observing and recording the children's visual behaviour and their ability to perform simple vision-guided tasks), visual evoked potentials (assessed by recording cortical electrophysiological responses to full-screen black-and-white flickering stimuli), and retinal structure (assessed with handheld optical coherence tomography [OCT] and widefield fundus imaging). To identify adverse effects, including inflammation and retinal detachment, we conducted ocular examinations using slit-lamp biomicroscopy and dilated fundoscopy. Safety was further assessed by testing of visual acuity, ophthalmoscopy, handheld OCT and widefield fundus imaging.
Findings
Patients were selected for treatment between July 12, 2019, and March 16, 2020. Before intervention, the children's binocular visual acuities were limited to perception of light. At a mean of 3·5 years (range 3·0–4·1) after intervention, the visual acuities of the children's treated eyes had improved to a mean of 0·9 logarithm of the minimal angle of the minimum angle of resolution ([logMAR] range 0·8–1·0); visual acuities before intervention were equivalent to 2·7 logMAR. In contrast, the visual acuities of the children's untreated eyes became unmeasurable at the final follow-up. In the two children able to comply with testing, an objective test of visual acuity confirmed improvements in visual function, and measurement of visual evoked potentials showed enhanced activity of the visual cortex, specific to the treated eyes. In three of the children, structural lamination of the outer retina was better preserved in the treated eye than in the untreated eye, and, for all four children, retinal thickness appeared better preserved in the treated eye than in the untreated eye. The treated eye of one child developed cystoid macular oedema. No other safety concerns were identified.
Interpretation
Our findings indicate that young children with AIPL1-related retinal dystrophy benefited substantially from subretinal administration of rAAV8.hRKp.AIPL1, with improved visual acuity and functional vision and evidence of some protection against progressive retinal degeneration, without serious adverse effects.
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