Voretigene Neparvovec (Luxturna) for Biallelic RPE65-Associated Retinal Dystrophy: Systematic Review.

Abstract

Biallelic RPE65-associated inherited retinal disorders (IRDs) cause progressive vision loss, impaired light sensitivity, and reduced mobility. Voretigene neparvovec-rzyl (LUXTURNA), the first FDA-approved gene therapy for this condition, is a disease-modifying option whose clinical benefits and harms warrant synthesis. Patients with biallelic RPE65-associated IRDs often have severe functional impairment despite variable BCVA changes. Understanding treatment effects on BCVA, light sensitivity, VF, and adverse events is essential for referral timing, counseling, and monitoring. Ovid MEDLINE, Embase, and the Cochrane Library were searched from January 2000 through October 2025 for randomized trials and observational studies evaluating voretigene neparvovec-rzyl in RPE65-associated IRDs. The primary outcome was BCVA; secondary outcomes included full-field stimulus threshold (FST), visual field (VF), and adverse events including chorioretinal atrophy and central retinal thickness (CRT) change. Findings were synthesized narratively for the systematic review, with random-effects meta-analyses for perifoveal atrophy incidence and CRT change where data allowed. Twenty-eight studies met inclusion criteria, encompassing 376 individuals and 673 treated eyes. BCVA outcomes were variable and generally modest, with somewhat greater gains in pediatric than adult cohorts. Light sensitivity improved consistently on FST, evident by 1 month and sustained through 6 months in the largest cohort (mean change -18.24 dB); one study reported greater 12-month gains in children (13 dB) than adults (8 dB). VF improved substantially in the pivotal trial cohort (92% mean increase at 1 year, sustained to 3-4 years), with more equivocal findings in real-world pediatric cohorts. Chorioretinal atrophy and intraocular inflammation were the most frequently reported adverse events. Pooled analysis of 3 studies estimated 75% of treated eyes (95% CI, 57%-89%) developed new or progressive perifoveal atrophy; CRT changes ranged from a mean increase of 8.3 µm to a decrease of 27.5 µm. Severe complications such as retinal tears and detachment were infrequent. Voretigene neparvovec-rzyl is associated with improvements in light sensitivity and VF in pediatric patients treated before advanced degeneration, while BCVA gains are variable and usually modest. Chorioretinal atrophy, including perifoveal atrophy in a majority of treated eyes, is a common structural finding warranting monitoring alongside functional benefits.