Gene Therapy for RPE65-RD Shows Functional Benefits, Structural Decline

Real-world data on 24-month outcomes of Luxturna is promising for patients with biallelic RPE65-associated retinal degeneration, reflecting a benefit to their visual function and quality of life. However, the therapy showed variable effects on visual acuity and an overall decrease in structural outcomes. Photo: Sherry Bass, OD. Click image to enlarge. Mutations in the RPE65 gene can cause early-onset inherited retinal dystrophies (IRDs), particularly Leber’s congenital amaurosis and retinitis pigmentosa. While uncommon, RPE65-associated retinal degeneration (RPE65-RD) has been linked to severe nyctalopia and often results in legal blindness by the 30s to 40s. One promising intervention is voretigene neparvovec (Luxturna, Spark Therapeutics), a one-time AAV2-based gene augmentation therapy that delivers a functional RPE65 gene. It was FDA approved in 2017. Clinical trials and real-world studies have shown improvements in light sensitivity and functional vision with a favorable safety profile. To bolster this evidence, a new prospective study conducted in Portugal assessed safety, structural and functional effectiveness and patient-reported outcomes over two years. Twelve patients (24 eyes; mean age 25.9 years) were treated bilaterally between May 2021 and February 2025. Eligible patients had confirmed biallelic pathogenic or likely pathogenic RPE65 variants, evidence of viable retinal cells on spectral-domain OCT (central foveal thickness >100µm), BCVA better than 20/800 and the ability to complete functional testing. Researchers analyzed structural, functional and patient-reported outcome data collected at baseline and up to two years post-treatment.Over 24 months, the treatment demonstrated “meaningful benefits in selected functional outcomes and quality of life, particularly in younger patients, despite variable effects on visual acuity and an overall decrease in structural (SD-OCT) outcomes,” the researchers wrote in a paper for the British journal Eye.Full-field stimulus testing showed an improvement in median thresholds from -2.2 at baseline to -3.9 at two years. This increase in light sensitivity was associated with reduced disability in mesopic peripheral function and reduced rod-function anxiety. Notably, BCVA declined by a median of six ETDRS letters from baseline, while visual field measures (mean deviation and foveal sensitivity) remained essentially unchanged. Patients younger than 30 years achieved better functional outcomes than those 30 years or older, underscoring the importance of earlier intervention. Additionally, structural retinal analysis showed progressive changes consistent with treatment-associated degeneration.The safety profile of Luxturna in this study aligns with prior reports. At least one adverse event was recorded in 91.7% of eyes, with most being considered mild and occurring within the first postoperative months. Foveal thinning and progression of preexisting atrophy were observed in some patients, but the researchers chalk this up to the severity of the underlying disease. They also pointed out that no severe complications (i.e., retinal detachment or endophthalmitis) were observed.Since multimodal imaging revealed new atrophic changes and/or progression of preexisting ones, this suggests that VN may not fully halt retinal degeneration, the researchers explained in their paper. “Chorioretinal atrophy (CRA) appeared at the injection site, in the treatment area, and in the retinal periphery, suggesting distinct pathophysiology mechanisms,” they wrote. While the CRA did not seem to compromise functional improvement, “the potential for atrophic lesion enlargement with subsequent foveal involvement raises concerns about its long-term outcomes,” they added, proposing the need for “continued monitoring and optimization of treatment strategies to minimize retinal damage while preserving therapeutic benefits.”Click here for the journal source. Machado T, Soares M, Raimundo M, et al. Structural, functional and patient-reported 24-month outcomes of voretigene neparvovec in Portuguese patients with RPE65-associated disease. Eye. 2026. [Epub ahead of print]. This article was developed by the editorial staff in conjunction with experts in the field. In the process, AI may have been among the editorial tools used to meet the goals of human editors, who approved all content.