Full-field Scotopic Threshold Improvement after Voretigene Neparvovec-rzyl Treatment Correlates with Chorioretinal Atrophy

Purpose: To analyze demographic and ophthalmic data in patients with and without chorioretinal atrophy after voretigene neparvovec-rzyl (VN) to identify possible causes for this phenomenon. Design: Retrospective cohort study with longitudinal follow-up. Participants: A total of 71 eyes of 38 patients aged 2 to 44 years with RPE65-mediated retinal dystrophy treated with VN across 2 large gene therapy centers in the United States and Germany. Methods: Patients treated with VN who developed atrophy were compared with those who did not. Main Outcome Measures: Gender, age, surgical center, spherical equivalent refraction, best-corrected vi-sual acuity (BCVA), baseline full-field scotopic threshold testing (FST), and posttreatment change in FST. Results: A total of 20 eyes of 12 patients developed atrophy after treatment with VN (28% of all eyes). There was no significant difference in gender, age, surgical center, or spherical equivalent refraction between the at-rophy group and the no atrophy group. However, patients between school age and young adulthood were predominantly affected, whereas the youngest and the oldest patients did not develop atrophy. Baseline BCVA was better in patients who developed atrophy than those who did not (P = 0.006). The postoperative improve-ment in FST at 1 month was significantly higher in the atrophy group than in the no atrophy group (P = 0.0005), and this difference remained statistically significant at 1 year (P = 0.0001). There was no correlation to baseline FST, to inflammation, or to which eye was treated first. Conclusions: The degree of FST improvement after VN appears to be strongly correlated with the devel-opment of VN-related chorioretinal atrophy. This finding raises the possibility that atrophy may develop as a toxic or metabolic sequela of vector-mediated RPE65 expression. In light of the expanding number of retinal gene therapy clinical trials, this complication warrants further study because it may not be limited to VN. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2023;130:764-770 & COPY; 2023 by the American Academy of Ophthalmology

Automated summary

This retrospective cohort study analyzed demographic and ophthalmic data in patients treated with voretigene neparvovec-rzyl (VN) and found that 28% of the patients developed chorioretinal atrophy, indicating a possible toxic or metabolic sequela of vector-mediated RPE65 expression. This finding has important implications for expanding retinal gene therapy clinical trials and warrants further investigation.