Researchers from the NIHR Moorfields Biomedical Research Centre and University College London have found that gene therapy improved visual acuity and preserved retinal structure in young children with AIPL1-associated severe retinal dystrophy. This is the first human trial of gene supplementation therapy targeting this condition.

Retinal dystrophy caused by biallelic variants in the AIPL1 gene leads to severe visual impairment from birth, with progressive degeneration and limited treatment options. Previous studies of early-onset rod-cone dystrophies, including AIPL1-related forms, highlighted a critical window for intervention during early childhood, when some photoreceptor structure remains intact. Prior research using Aipl1-deficient mouse models and human retinal organoids demonstrated partial restoration of photoreceptor function through gene therapy.

In the study, “Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study,” published in The Lancet, researchers administered a single subretinal injection of a recombinant adeno-associated viral vector (rAAV8.hRKp.AIPL1) carrying the AIPL1 gene to one eye of each child to assess the safety and efficacy of gene supplementation therapy in improving visual function and preserving retinal structure.

Four children aged 1.0 to 2.8 years with confirmed AIPL1 mutations received a subretinal injection of rAAV8.hRKp.AIPL1 in one eye. The gene therapy vector, produced under UK regulatory approval, delivered the AIPL1 coding sequence using a human rhodopsin kinase promoter. Oral prednisolone was administered perioperatively to mitigate inflammation. Visual acuity, functional vision, retinal structure, and cortical responses were evaluated over a mean follow-up of 3.5 years.

Before treatment, all children exhibited visual acuity limited to light perception. By the final follow-up, treated eyes showed a mean visual acuity improvement to 0.9 logMAR (range 0.8–1.0) from a baseline equivalent of 2.7 logMAR.

Untreated eyes of the children showed no improvement in visual acuity and either deteriorated to unmeasurable levels or lost light perception by the final follow-up.

Objective testing in two older children using the PopCSF touchscreen assay and steady-state visually evoked potentials (ssVEPs) confirmed significant enhancements in visual function and cortical response specific to treated eyes. Retinal imaging revealed better-preserved thickness and lamination in three treated eyes compared to untreated counterparts.

Gene therapy with rAAV8.hRKp.AIPL1 resulted in sustained visual improvements without serious adverse effects, supporting early intervention for AIPL1-associated retinal dystrophy.