In an open-label, first-in-human study, researchers evaluated the safety and efficacy of gene therapy in pediatric patients with AIPL1-associated severe retinal dystrophy, a rare genetic disorder that causes early-onset blindness. The study demonstrated substantial improvements in visual acuity and functional vision, suggesting that early intervention with gene therapy may protect against progressive retinal degeneration.

Led by Michel Michaelides, MD, Professor at the UCL Institute of Ophthalmology at the University College London, the researchers conducted a nonrandomized, single-arm clinical trial at Moorfields Eye Hospital and Great Ormond Street Hospital for Children in London. The study, which was recently published in The Lancet, enrolled four children aged 1 to 2.8 years with biallelic disease-causing mutations in the AIPL1 gene.

A recombinant adeno-associated viral (rAAV8) vector carrying the AIPL1 coding sequence was administered via subretinal injection to one eye per child. The children received oral prednisolone to mitigate inflammation. The researchers assessed safety and efficacy using visual acuity tests, functional vision observations, visual evoked potentials (VEPs), and retinal imaging, including handheld optical coherence tomography (OCT) and widefield fundus imaging.

At an average follow-up of 3.5 years (range = 3 to 4.1 years), the researchers reported the following results:

• Prior to treatment, all four children had vision limited to light perception (equivalent to 2.7 logMAR). Following intervention, treated eyes showed improvements to a mean of 0.9 logMAR (range = 0.8 to 1), while untreated eyes became unmeasurable at final follow-up.
• Parents and clinicians observed increased object recognition, improved mobility, and better engagement in vision-guided tasks in all four children.
• In two children who could undergo testing, cortical electrophysiologic responses were enhanced specifically in the treated eyes, which supported functional improvements.
• OCT imaging showed better-preserved retinal thickness and outer retinal lamination in the treated eyes compared with the untreated eyes in three of the four children.
• One child developed cystoid macular edema in the treated eye, which partially regressed over time. No other safety concerns, such as significant inflammation or retinal detachment, were reported.

The researchers noted that children may be at greater risk for inflammation following the intraocular injection of the AAV vector, given their predisposition to other postoperative inflammation compared with adults. However, the perioperative steroids seemed to mitigate any inflammatory outcomes.

“The outcomes observed for the treated eyes would not be expected from the natural history of AIPL1-associated severe retinal dystrophy, which is characterized by rapid, inexorable progression,” the study authors wrote. “Visual acuity better than 1.5 logMAR [is] exceptional for individuals with this condition,” they added.

Limitations of the study included the low number of treated patients, absence of a control group, and expected challenges of getting reliable visual function measurements in young children with severe sight impairment. However, the researchers noted: “promising evidence of benefit is provided by the magnitude of improvements in visual function, the specificity of this effect for the treated eye in each child, and the objective evaluation of visual acuity, outer retinal lamination, and cortical responses.”

Early gene therapy for inherited retinal diseases may offer the highest likelihood of benefit in neurodevelopment and social behavior, as well as better psychosocial outcomes because of retinal viability and neuronal plasticity, the researchers concluded.

A full list of disclosures can be found in the published research