Abstract
Purpose :
Gene therapy's emergence holds promise in reversing or preventing further vision deterioration in patients with incurable inherited retinal degeneration (IRD). Luxturna provides hope for visual restoration in RPE65 mutation-related IRD, yet global accessibility remains limited. Consequently, we conducted the initial phase I trial to evaluate the safety and efficacy of gene therapy on retinal and visual functions in RPE65-related IRD patients in China.
Methods :
Design: Open-label phase 1 follow-on clinical trial.
Methods: Retinal and visual functions were evaluated in 9 patients (mean age 25.11±10.03 years, 11-39 years) with RPE65-associated IRD. A subretinal injection of adeno-associated virus (AAV) containing the crucial isomerohydrolase-encoding gene (rAAV2-hRPE65) was administered in the most severely impaired eye. Three young adults (28-30 years) with RPE65-IRD received a low-dose subretinal injection (7.5 x 10^10 vector genomes in 300 µl), while two children (11 and 12 years) and four adults (19-39 years) received a high dose (1.5 x 10^11 vector genomes in 300 µl). All patients underwent up to 1-year follow-up examinations.
Results :
rAAV-hRPE65 exhibited excellent tolerability, with no serious adverse events or immune responses detected. Mild adverse events during the initial two weeks post-operation included conjunctival congestion or hemorrhage related to the procedure, and intraocular hypertension linked to glucocorticoid use. One year post-administration, mean (SD) MLMT lux score change was 2.89 (1.36) scores, BCVA increased by 13.44 (9.07) letters, and FST improved by 2.3 (1.37) log units. Notably in the high-dose group, BCVA improved by 15.67 (8.12) letters, FST increased by 3.21 (0.32) log units, and MLMT improved by 3.33 (0.82) scores. High-dose group visual function significantly surpassed the low-dose group, all experiencing increased ambulatory vision. FST's sensitivity in detecting subtle vision improvements post-intervention is particularly noteworthy.
Conclusions :
The safety, extent, and stability of vision improvement in all patients substantiate the utilization of AAV-mediated gene therapy for the treatment of inherited retinal diseases, with judicious dosage administration yielding optimal potential gains.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.