Study demonstrates visual acuity improvements following gene therapy for AIPL1-associated inherited retinal dystrophies

Prior to intervention, all patients' visual acuity was limited to perception of light, but the treated eyes improved following the therapy. Image credit: ©DragonImages – stock.adobe.com

A new study published in The Lancet evaluates a gene supplementation therapy for patients with retinal dystrophies such as Leber congenital amaurosis (LCA) associated with AIPL1 gene variations. Patients were treated with a recombinant adeno-associated viral vector comprising the human AIPL1 coding sequence driven by a human rhodopsin kinase promoter region (rAAV8.hRKp.AIPL1). The study was funded by the UK National Institute for Health Research and Moorfields Eye Charity, and led by investigators from NIHR Moorfields Biomedical Research Centre and Great Ormond Street Hospital for Children, both in London, UK.¹

Michel Michaelides, MD, and his colleagues assessed four children with AIPL1-related, early-onset inherited retinal dystrophies. Prof Michaelides is a consultant ophthalmologist in medical retina, inherited eye disease and paediatric ophthalmology at Moorfields Eye Hospital, and a professor of ophthalmology at the University College London Institute of Ophthalmology.

According to reporting from the BBC, the patients were enrolled in the trial after being diagnosed with LCA and came from the United States, Turkey and Tunisia to undergo treatment.² Ethics approval for the study was limited to four participants; as such, the investigators enrolled four children, between 1 and 2.8 years old, with congenital severe retinal dystrophies and biallelic, disease-causing AIPL1 variants. All four patients had relative preservation of outer retinal structure at the start of treatment, as determined by optical coherence tomography (OCT) imaging.¹

Prior to intervention, the patients performed a series of tasks to test functional vision, which included object location and mobility tests. Visual acuity (VA) tests were administered for both eyes and for each eye independently with age-appropriate testing methods. Before administration of rAAV8.hRKp.AIPL1, when VA was tested, all four children demonstrated perception of light only.

Investigators administered rAAV8.hRKp.AIPL1 to one eye of each patient by subretinal injection, while the contralateral eye remained untreated for safety. Patients were also prescribed an oral surgery prior to surgery and in the 5 weeks following surgery to prevent inflammation.

At follow up appointments 3 to 4 years after treatment, the visual acuities of patients’ treated eyes showed significant improvement. “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,” the investigators wrote. “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.”

One patient developed cystoid macular oedema in the treated eye. No other safety concerns were reported. “OCT imaging showed relative preservation of outer retinal lamination in the treated eyes of three children at the ages of 4.5 years, 5.0 years, and 6.2 years,” the authors reported. These findings were consistent with the improvements in VA and suggested a protective benefit from degeneration, the study's authors remarked.¹

“The outcomes observed for the treated eyes would not be expected from the natural history of AIPL1-associated severe retinal dystrophy, which is characterised by rapid, inexorable progression, with visual acuity better than 1.5 logMAR being exceptional for individuals with this condition,” the investigators stated. “Spontaneous improvement in visual function has not been reported and would not be expected, given the progressively severe atrophy of the congenital remnant central macula during the first years of life.” The untreated contralateral eyes of the patients showed no improvement, though VA was symmetrical prior to intervention.

The investigators explained that the therapy was produced under special dispensation from the UK Medicines and Healthcare products Regulatory Agency. “In the absence of a clinical trial, we made this innovative experimental product available to children with confirmed mutations in AIPL1 under a Specials Licence with the approval of the Paediatric Bioethics Service at Great Ormond Street Hospital for Children,” they explained.

Reporters from the BBC spoke with Prof Michaelides, who said the research team will continue to monitor the patients and document any further changes in VA or eye structure. "The outcomes for these children are hugely impressive and show the power of gene therapy to change lives,” Prof Michaelides stated.²

References

1. Michaelides M, Laich Y, Wong SC, et al. Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study. The Lancet. 10.1016/S0140-6736(24)02812-5.

2. Mundasad S. 'Life-changing' gene therapy for children born blind. BBC. Published February 20, 2025. Accessed February 25, 2025. https://www.bbc.com/news/articles/c5ydnz2d75xo