First analysis of gene therapy for RPE65 inherited retinal dystrophies shows good safety, efficacy

French researchers, led by Dr Isabelle Audo reported that voretigene neparvovec (VN) (Luxturna, Spark Therapeutics), used to treat patients with a RPE65-related inherited retinal dystrophy, showed good safety and efficacy at the 1-year time point of the LIGHT Study.

Dr Isabelle Audo

Dr Audo is professor of ophthalmology in the Department of Genetics at Institut de la Vision, and coordinator of the National rare disease centre at Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris.

Mutations in the RPE65 gene and loss of gene function causes photoreceptor dysfunction and degeneration, leading to blindness. VN is the first gene therapy for this patient population.

The LIGHT study, Dr Audo described, is a descriptive, non-interventional study in which VN was administered at a dose of 1.5 x 1011 vector genomes that were delivered in a total subretinal volume of 0.3 ml.

Both eyes of the patients were treated on separate days and at least 6 days apart. Follow-up examinations were conducted at 1, 3-, 6-, 12- and 24-months following gene therapy in the second eye. At these time points, the investigators evaluated the treatment efficacy and safety and collected the patients’ postoperative experience.

The efficacy was assessed by measuring the visual acuity (VA), full-field stimulus threshold (FST), and visual fields (VF). A maze platform was used that showed a typical street that patients may encounter during daily activities. Patients were instructed to follow the path under four lighting conditions of 2, 7.5, 50, and 500 lux and avoid obstacles and walls. Their mobility was assessed using the percentage of preferred walking speed and the time to completion of the course completion time.

The investigators also collected patient/parent comments about the visual experience.

LIGHT study results

Twelve patients (6 adults, 6 children; age range, 4-35 years) were included.

Eleven had a diagnosis of Leber congenital amaurosis and one had retinitis pigmentosa. All have undergone bilateral surgeries.

At the 1-month evaluation, Dr Audo reported that the FST had median decrease of -33.2 decibels (dB) (-33.7; -19.8) dB, which remained stable until the last assessment. The VFs and VAs did not change significantly.

She also reported that the percentage of preferred walking speed at 2 lux and at high speed, 1 month after surgery had a median increase of 63.9% (47.8%; 88.5%) and the course completion time decreased by 47.23% ( -58.50 %; -41.16 %). These improvements continued over time.

At least one adverse effect related to surgery occurred in all patients and only 1 was serious, i.e., a retinal detachment. Seven patients had at least one adverse effect related to VN, all of which were not serious and did not require treatment. Chorioretinal atrophy was observed in both eyes of 5 patients and was considered to be possibly related to surgery and VN.

The patients’ comments highlighted three categories described by Kay et al. 2021 mentioned by more than 50% of the patients: visual function symptoms, impact on vision dependent activities of daily living, and coping mechanisms and visual aids, providing more insight into their postoperative experience.

Dr Audo said, “This experience with VN showed significant post-treatment improvements in FST from month 1. Adding a mobility test to assess the evolution of functional vision in their routine follow-up protocol in addition to the FST allows this study to gain further insight into the efficacy of VN during the first postoperative year. The patients’ mobility also improved from the first month after surgery for all patients.”

She also mentioned that in the 5 patients in which chorioretinal atrophy developed after VN treatment, the FST improved compared to baseline and remained stable over the long-term follow-up (between 12- and 24-months post VN treatment).