Development of retinal atrophy after subretinal gene therapy with voretigene neparvovec

Author:

Reichel Felix FriedrichORCID,Seitz ImmanuelORCID,Wozar Fabian,Dimopoulos Spyridon,Jung Ronja,Kempf Melanie,Kohl Susanne,Kortüm Friederike CharlotteORCID,Ott Saskia,Pohl Lisa,Stingl KrunoslavORCID,Bartz-Schmidt Karl Ulrich,Stingl KatarinaORCID,Fischer M. Dominik

Abstract

Background/aimsVoretigene neparvovec (VN) is the first and only subretinal gene therapy approved by the Food and Drug Administration and European Medicines Agency. Real-world application has started in 2018 in patients with vision impairment due to biallelic retinal pigment epithelium (RPE) 65 mutation-associated inherited retinal degenerations. Herein, we evaluated the development of retinal atrophy within in a single-centre patient cohort treated with VN.Methods13 eyes of eight patients treated with VN were retrospectively analysed for areas of retinal atrophy over a period of 6–24 months following surgery. Ultrawide field images were used to measure the area of atrophy. Fundus autofluorescence imaging is presented as an instrument for early detection of signs of retinal atrophy in these patients.ResultsAtrophic changes beyond the retinotomy site were observed in all eyes. Areas of atrophy developed within the area of detachment (bleb) in all eight patients and outside the bleb in three patients. Changes in autofluorescence preceded the development of retinal atrophy and were already evident 2 weeks after surgery in the majority of patients. The areas of atrophy increase with time and progression continued over year 1. Functional outcomes remained stable (VA, FST, visual field).ConclusionSubretinal injection of VN can lead to RPE atrophy with consequent photoreceptor loss in and outside of the bleb area. Fundus autofluorescence is an important tool to monitor atrophic changes in patients after gene therapy. Interestingly, while areas of atrophy also included central areas, the functional benefits of the treatment did not appear to be affected and remained stable.

Publisher

BMJ

Subject

Cellular and Molecular Neuroscience,Sensory Systems,Ophthalmology

Reference25 articles.

1. The natural history of inherited retinal dystrophy due to biallelic mutations in the RPE65 gene;Chung;Am J Ophthalmol,2019

2. Longitudinal and cross-sectional study of patients with early-onset severe retinal dystrophy associated with RPE65 mutations

3. Chung DC , Lee K , Reape KZ . Long-Term effect of Voretigene Neparvovec on the Full-Field light sensitivity threshold test of patients with RPE65 mutation-associated inherited retinal dystrophy – post hoc analysis of phase I trial data. Invest Ophthalmol Vis Sci 2019;60:3398.

4. Durability of Voretigene Neparvovec for biallelic RPE65-Mediated inherited retinal disease: phase 3 results at 3 and 4 years;Maguire;Ophthalmology,2021

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