Structural, functional and patient-reported 24-month outcomes of voretigene neparvovec in Portuguese patients with RPE65-associated disease

Voretigene neparvovec (VN) is a one-time gene therapy for biallelic RPE65-associated retinal degeneration (RPE65-RD). This study evaluated the real-world safety, effectiveness, and patient-reported outcomes (PRO) of VN in Portuguese patients over 2 years.

Prospective, single-centre study conducted between May 2021 and February 2025. Structural, functional, and PRO data were collected from eligible patients at baseline, and during efficacy and durability follow-up visits up to 2 years post-treatment.

The study analysed 24 eyes from 12 patients (mean age: 25.9 years; 66.7% aged <30 years). Functional assessment by full-field stimulus testing (FST) showed improvement in the median [P25;P75] thresholds, from -2.2 [-3.1; -1.9] at baseline to -3.9 [-4.5;-3.2] log(cd.s/m²) after 2 years. This improvement correlated with reduced disability in mesopic peripheral function (r = 0.767, p = 0.016) and rod-function anxiety (r = 0.667, p = 0.050). Best-corrected visual acuity decreased by a median of 6 ETDRS letters [-20.0; 2.2] compared to baseline (55.5 [41.2; 69.2] vs. 36.0 [23.8; 58.0], p = 0.030), while visual field function remained stable (mean difference from mean: p = 0.070; fovea sensitivity: p = 0.688). Patients aged <30 years achieved better functional outcomes than those ≥30. Structural analysis of the retina revealed changes suggestive of treatment-induced degeneration. At least one adverse event occurred in 91.7% of eyes, mostly within the first postoperative months.

Our findings reinforce the effectiveness and safety of VN for RPE65-RD under real-world conditions. We demonstrate functional benefits on FST and an acceptable safety profile of VN, while establishing a meaningful and positive relationship between visual function and patients' quality of life (QoL), particularly in younger patients. Structural decline and BCVA loss suggest that the therapy may not fully arrest the natural disease progression, despite the significant increase in light sensitivity and QoL maintained through 2 years.