Retinal gene therapy in RPE-65 gene mediated inherited retinal dystrophy
Open accessAbstract
Background 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.Methods 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.Results 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.Conclusions 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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Both mild and fulminant inflammation may occur as early as two weeks after subretinal injection, which appears to be more likely with higher vector doses.
“However, both mild and fulminant inflammation may occur as early as two weeks after subretinal injection, which appears to be more likely with higher vector doses (Weleber et al., 2016; Jalil et al., 2023; Michaelides et al., 2023).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Jalil et al., 2023
The Discussion reports mild inflammatory macular oedema in one eye two weeks after subretinal therapy and a more severe, probably immune-mediated reaction in the second eye at two weeks. It does not link inflammation to higher vector doses; instead, it suggests prior immune sensitisation may explain the worse reaction in the second eye. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThere have been several cases of severe intraocular inflammation in the second eye following voretigene neparvovec administration in the first eye several weeks before, sometimes with detrimental consequences for vision.
“Furthermore, there have been several cases of severe intraocular inflammation in the second eye following voretigene neparvovec administration in the first eye several weeks before, sometimes with detrimental consequences for vision (Jalil et al., 2023) (Fig. 2G, B. Leroy & F. Nerinckx, personal communication, Nov. 2024).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Jalil et al., 2023
The Results and Discussion (pages not provided) describe one patient whose second eye developed marked macular oedema after voretigene neparvovec treatment, followed by permanent loss of foveal photoreceptors and reduced central vision. The paper supports a probable immune-mediated complication after treatment of the first eye, but it does not document several cases of severe intraocular inflammation; the exact interval between eye treatments is not stated in the cited passages. (LLM, conf=0.88)
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Cites
Russell, S., Bennett, J., Wellman, J. A., Chung, D. C., Yu, Z.-F., Tillman, A., Wittes, J., Pappas, J., Elci, O., McCague, S., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31868-8 · Cited by 1,952 · see citing works
Maguire, A. M., High, K. A., Auricchio, A., Wright, J. F., Pierce, E. A., Testa, F., Mingozzi, F., Bennicelli, J. L., Ying, G.-S., Rossi, S., et al. (2009) · The Lancet · doi:10.1016/s0140-6736(09)61836-5 · Cited by 865 · see citing works
Gene Therapy for Human Genetic Disease?
Friedmann, T., & Roblin, R. O. (1972) · Science · doi:10.1126/science.175.4025.949 · Cited by 819 · see citing works
Leber congenital amaurosis: Genes, proteins and disease mechanisms
den Hollander, A. I., Roepman, R., Koenekoop, R. K., & Cremers, F. P. M. (2008) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2008.05.003 · Cited by 811 · see citing works
National Institute for Health and Care Excellence.
Cowie, M. (2015) · PubMed · Cited by 651 · see citing works
Bennett, J., Wellman, J., Marshall, K. A., McCague, S., Ashtari, M., DiStefano-Pappas, J., Elci, O. U., Chung, D. C., Sun, J., Wright, J. F., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)30371-3 · Cited by 461 · see citing works
Maguire, A. M., Russell, S., Wellman, J. A., Chung, D. C., Yu, Z.-F., Tillman, A., Wittes, J., Pappas, J., Elci, O., Marshall, K. A., et al. (2019) · Ophthalmology · doi:10.1016/j.ophtha.2019.06.017 · Cited by 409 · cited 2× · see citing works
“In addition, it correlates well with navigation under dim illumination [10].”
BackgroundPathology and pathogenesis of retinal detachment
Ghazi, N. G., & GREEN, W. R. (2002) · Eye · doi:10.1038/sj.eye.6700197 · Cited by 302 · see citing works
Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy
Cideciyan, A. V. (2010) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2010.04.002 · Cited by 256 · see citing works
Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration.
Thompson, D. A., Gyűrűs, P., Fleischer, L. L., Bingham, E. L., McHenry, C. L., Apfelstedt-Sylla, E., Zrenner, E., Lorenz, B., Richards, J. E., Jacobson, S. G., et al. (2000) · PubMed · Cited by 250 · see citing works
Retinal reattachment of the primate macula. Photoreceptor recovery after short-term detachment.
Guérin, C. J., Anderson, D. H., Fariss, R. N., & Fisher, S. K. (1989) · PubMed · Cited by 84 · see citing works
Deng, C., Zhao, P. Y., Branham, K., Schlegel, D., Fahim, A. T., Jayasundera, T. K., Khan, N., & Besirli, C. G. (2022) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-021-05508-2 · Cited by 64 · see citing works
Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina
Chandler, L. C., McClements, M. E., Yusuf, I. H., Martinez-Fernandez de la Camara, C., MacLaren, R. E., & Xue, K. (2021) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2021.05.011 · Cited by 43 · cited 1× · see citing works
“This is in contrast to the type-1 cellmediated effector immunity response that has been previously implicated with subretinal gene therapy in murine eyes [12], Either way, a temporary increase in oral steroids immediately settled the macular oedema and the photoreceptor layer at the fovea remained unaffected.”
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Flagged first, then by citations
Cited by
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A systematic review of immunosuppressive protocols used in AAV gene therapy for monogenic disorders
Vrellaku, B., Hassan, I. S., Howitt, R., Webster, C. P., Harriss, E., McBlane, F., Betts, C., Schettini, J. L., Lion, M., Mindur, J. E., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.07.016 · Cited by 79 · see citing works
Testa, F., Bacci, G. M., Falsini, B., Iarossi, G., Melillo, P., Mucciolo, D. P., Murro, V., Salvetti, A. P., Sodi, A., Staurenghi, G., et al. (2024) · Eye · doi:10.1038/s41433-024-03065-6 · Cited by 35 · see citing works
Tripepi, D., Jalil, A., Ally, N., Buzzi, M., Moussa, G., Rothschild, P.-R., Rossi, T., Ferrara, M., & Romano, M. R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310535 · Cited by 31 · see citing works
Self-citationFull-field stimulus threshold testing: a scoping review of current practice
Shi, L., Hall, A. J., & Thompson, D. (2023) · Eye · doi:10.1038/s41433-023-02636-3 · Cited by 27 · see citing works
Purdy, R., John, M., Bray, A., Clare, A. J., Copland, D. A., Chan, Y. K., Henderson, R. H., Nerinckx, F., Leroy, B. P., Yang, P., et al. (2025) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2025.101354 · Cited by 24 · see citing works
Malvasi, M., Casillo, L., Avogaro, F., Abbouda, A., & Vingolo, E. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813756 · Cited by 21 · see citing works
Gene therapy strategies in ophthalmology—an overview of current developments and future prospects
Krajewska, J. B., & Waszczykowska, A. (2025) · Journal of Applied Genetics · doi:10.1007/s13353-025-00973-5 · Cited by 17 · see citing works
Foveal detachment in voretigene neparvovec administration: essential step or avoidable risk?
Király, P., Ivanova, T., & Jalil, A. (2025) · Eye · doi:10.1038/s41433-025-03672-x · Cited by 4 · see citing works
Self-citationReal-world outcomes of Voretigene Neparvovec: a single-centre consecutive case series
Jalil, A., Ferrara, M., Lippera, M., Parry, N. R. A., Black, G. C. M., Banderas, S., Ashworth, J. L., Biswas, S., Hall, G., Gray, J., et al. (2025) · Eye · doi:10.1038/s41433-025-03637-0 · Cited by 4 · see citing works
Self-citationCenachi, S. P. D. F., Frasson, M., Mares, V., Arantes, R. R., Albuquerque, A. L. B., Nascentes, A. L. M., de Marco, L. A. C., & Nehemy, M. B. (2025) · Molecular vision · doi:10.63500/mv_v31_45 · Cited by 2 · see citing works
Genetic Analysis of Choroideremia-Related Rab Escort Proteins
Xing, Z., Wu, F., Gomez, E. C., Pao, A., Gao, L., Douglas, A., Li, Y., Spernyak, J. A., Wong, G. W., Singh, P. K., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26083636 · Cited by 1 · see citing works
Langer, P. M., Clare, A. J., Peng, X., Costello, K. L., Cendanawati, S., Wilson, L. L., Ward, A., Bell, O. H., Chu, C. J., Chan, Y., et al. (2026) · Molecular Therapy · doi:10.1016/j.ymthe.2026.02.018 · Cited by 1 · see citing works
Terapia génica en la Argentina, ¿es posible?
Mancini, J. E., & Saravia, M. (2023) · Oftalmología clínica y experimental. · doi:10.70313/2718.7446.v16.n04.257 · Cited by 1 · see citing works
(2023) · Reactions Weekly · doi:10.1007/s40278-023-43444-1
The molecular renaissance: Navigating the biological boundaries of vision
Kumaramanickavel, G. (2026) · Indian Journal of Ophthalmology · doi:10.4103/ijo.ijo_143_26
Voretigene Neparvovec (Luxturna) for Biallelic RPE65–Associated Retinal Dystrophy: Systematic Review
Butt, A. B., Zaman, M., Mihalache, A., KamaliZonouzi, S., Zadeh, P. B., Shah, Y. R., Popovic, M. M., Kertes, P. J., Ballios, B. G., Vincent, A., et al. (2026) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2026.08.043
- Authors
- Jalil, A., Ivanova, T., Moussa, G., Parry, N. R. A., & Black, G. C. M.
- Affiliations
- Manchester Royal Eye Hospital (GB)
- Corresponding author
- Jalil, Assad
- Venue
- Eye
- Published
- 2022-09-26
- Volume
- 37
- Issue
- 9
- Pages
- 1874-1877
- ISSN
- 0078-5334 (ISSN-L)
- 0950-222X
- 1476-5454
- PMC
- PMC10275908
- OpenAlex
- W4297224647
- Cited by
- 16
- References
- 13
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 2 · 2023: 5
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Eye (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- retinal gene therapy, voretigene neparvovec, RPE65 mutations, inherited retinal disease, rod photoreceptor function, low luminance vision, subretinal injection, vector immunogenicity
- MeSH terms
- Humans, Mutation, Retina, Vision, Ocular, Visual Acuity, Genetic Therapy, Vision, Low, Tomography, Optical Coherence, Retinal Dystrophies
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