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Retinal gene therapy in RPE-65 gene mediated inherited retinal dystrophy



Voretigene neparvovec (VN) is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. We illustrate, both the benefits and pitfalls associated with ocular gene therapy in the same patient.


Two eyes of one patient with bi-allelic RPE65 mutations have been treated with VN. The clinical examinations included visual acuity (VA, in normal and low luminance), colour vision, contrast sensitivity, International Society for Clinical Electrophysiology of Vision (ISCEV) standard retinal electrophysiology and dark-adapted full-field stimulus threshold (FST), Goldmann VF analysis and imaging studies, including optical coherence tomography (OCT) and autofluorescence. These were performed at baseline, 2-weeks, 3 and 6-months, 1 and 2-years follow-up.


The first eye showed improvement in rod photoreceptor function with increased peripheral and low luminance vision (baseline VA: 0.9 logMAR and 2-years post-operative VA: 0.7 logMAR). The second eye, whilst showing increased light sensitivity, suffered a drop in central vision (at 2-weeks) with loss of foveal photoreceptors as shown by the loss of ellipsoid zone on OCT scan (baseline VA: 0.6, 2-year post-operative VA: 1.2). FST improvements were maintained in both eyes indicating a sustained efficacy of VN with little waning of its effect.


We present a previously unreported adverse complication of subretinal VN therapy in bi-allelic RPE65, indicating a probable immune response in treatment of the second eye, resulting in loss of foveal photoreceptors. This case-series highlights the potential and pitfalls of retinal gene therapy in the same patient. The immune responses of the body to a ‘foreign vector’, remains a challenge.

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Fig. 1: Fundus picture of the patient.
Fig. 2: OCT of the left eye.
Fig. 3: OCT of the right eye.
Fig. 4: Baseline and post-surgical measures of visual function.

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The raw data are available upon reasonable request.


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All authors have made substantial contributions to the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.

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Correspondence to Assad Jalil.

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The authors declare no competing interests.

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As this was a retrospective anonymized study, as per our local protocol from our Clinical Effectiveness Department, and as per national guidelines from the National Code of Clinical Research, and the Health Research Authority (HRA), this study has ethical approval exemption and no patient consent was required for participation. All procedures were completed prior to the design of this study. Patients were diagnosed and treated according to local guidelines and agreements and written consent from patients was acquired prior to all procedures as clinically indicated. This study does not report on the use of new or experimental protocols.

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Jalil, A., Ivanova, T., Moussa, G. et al. Retinal gene therapy in RPE-65 gene mediated inherited retinal dystrophy. Eye (2022).

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