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Long-Term Effect of Gene Therapy on Leber’s Congenital Amaurosis
Open accessAbstract
BACKGROUND: Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS: We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS: Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS: Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).
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In the citing paper
“ocular AAV therapies leading to a permanent reduction in visual acuity following intraocular inflammation (9–11)”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [9]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“AAV dose-dependent intraocular inflammation and a few instances of persistent loss of visual acuity have been independently reported in clinical trials following subretinal AAV administration despite prophylactic immunosuppression (9–11).”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [9]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In the phase 1/2 dose-escalation trials for RPE65-associated LCA, choroideremia, and retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa, patients receiving higher doses of AAV have presented with various signs of retinal inflammation, including vitritis, retinitis, and choroiditis,2,6,7 implicating the presence of a cell-mediated immune response.”
From Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina (2021) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Despite the perceived low immunogenicity of AAV and relative immune privilege of the intraocular environment,8 dose-dependent retinal inflammation, or gene therapy-associated uveitis (GTAU), has been observed in many retinal gene therapy trials, which limits the vector dose and therapeutic efficacy.”
From Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina (2021) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Despite a 28-day oral corticosteroid therapy started 2 days before the first IVT, a regimen similar to that provided in several other clinical studies using IVT or sub-retinal AAV-based gene therapies,41–45 70.7% of lenadogene nolparvovec-treated eyes developed some degree of intraocular inflammation versus 10.2% of placebo-treated eyes.”
From Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy (2023) · cites this paper as [45]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This is clinically important as intraocular inflammation could lead to irreversible loss of retinal cells, deterioration of visual function and reduced durability of treatment effect associated with a costly one-off treatment.”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bainbridge et al., 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The intraocular inflammation is dose-dependent and can sometimes last for months or even years following treatment, leading to irreversible retinal structural damage and reduced visual function if uncontrolled (Bainbridge et al., 2015).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bainbridge et al., 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The intraocular inflammation is dose-dependent and can sometimes last for months or even years following treatment, leading to irreversible retinal structural damage and reduced visual function if uncontrolled (Bainbridge et al., 2015).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bainbridge et al., 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Notably, one participant developed anterior uveitis at 2 weeks, followed by CRA and reduced visual acuity by 6 months.”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bainbridge et al., 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Two participants developed optic disc swelling, retinal vascular tortuosity/sheathing and mild vitritis.”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bainbridge et al., 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Three out of eight participants who received the higher dose of vector (1 × 10 12 vg/eye) but none in the lower dose cohort (1 × 10 11 vg/eye) developed intraocular inflammation despite prophylactic peri-operative immunosuppression.”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bainbridge et al., 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Consequently, GTAU is often diagnosed shortly after the withdrawal of systemic immunosuppression prophy laxis (Dimopoulos et al., 2018) or when the dose reaches around 15 -20 mg for slower tapers, and sometimes several weeks to months after vector administration (Bainbridge et al., 2015).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bainbridge et al., 2015
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Although adeno-associated viral (AAV) vector-mediated retinal gene therapies have demonstrated efficacy”
From Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina (2021) · cites this paper as [2]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“The intraocular inflammation is dose-dependent and can sometimes last for months or even years following treatment, leading to irreversible retinal structural damage and reduced visual function if uncontrolled (Bainbridge et al., 2015).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bainbridge et al., 2015
Experimental — accuracy not yet measuredIn the citing paper
“In phase I/II clinical trials for RPE65-LCA at University College London (ClinicalTrials.gov: NCT00643747), ocular inflammation was noted following SRI of 1 × 1012 vg of AAV2-RPE65.71,99”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [99]
In the citing paper
“subfoveal viral gene therapy has been associated with various adverse effects, such as RPE alterations, retinal thinning, foveal morphological changes, vision loss, and the variable duration of clinical effects [281,294,296,297,298].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [296]
In the citing paper
“Dose-dependent immune responses have also been observed, with high doses potentially leading to persistent inflammation and clinically significant vision loss in patients receiving high-dose AAV2 vector-based subretinal RPE65 therapy [296].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [296]
In the citing paper
“However, some adverse events linked to the glucocorticoids themselves have already been described in retinal rAAV trials which point out the need for other alternatives to mitigate the inflammation [37].”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [37]
In the citing paper
“The results showed that retinal sensitivity was improved; however, the final transgene expression in the participants from the high dose group was adversely affected by ocular inflammation or immune responses [48].”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [48]
In the citing paper
“Nonetheless, inflammatory reactions to gene therapy in the eye have led to permanent vision loss for some patients7–9.”
From Investigation of Cas9 Antibodies in the Human Eye (2022) · cites this paper as [7]
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Metadata
- Authors
- Bainbridge, J. W. B., Mehat, M. S., Sundaram, V., Robbie, S. J., Barker, S. E., Ripamonti, C., Georgiadis, A., Mowat, F. M., Beattie, S. G., Gardner, P. J., Feathers, K. L., Luong, V. A., Yzer, S., Balaggan, K., Viswanathan, A., de Ravel, T. J. L., Casteels, I., Holder, G. E., Tyler, N., Fitzke, F. W., Weleber, R. G., Nardini, M., Moore, A. T., Thompson, D. A., Petersen-Jones, S. M., Michaelides, M., van den Born, L. I., Stockman, A., Smith, A. J., Rubin, G., & Ali, R. R.
- Affiliations
- Moorfields Eye Hospital (GB)
- Michigan State University (US)
- University of Michigan (US)
- Rotterdam Eye Hospital (NL)
- Universitair Ziekenhuis Leuven (BE)
- Oregon Health & Science University (US)
- ORCID
- Bainbridge, James W.B.
- Sundaram, Venki
- Robbie, Scott J.
- Georgiadis, Anastasios
- Mowat, Freya M.
- Beattie, Stuart G.
- Yzer, Suzanne
- Balaggan, Kamaljit
- Viswanathan, Ananth
- Casteels, Ingele
- Holder, Graham E.
- Tyler, Nick
- Weleber, Richard G.
- Moore, Anthony T.
- Thompson, Debra A.
- Michaelides, Michel
- Smith, Alexander J.
- Rubin, Gary
- Ali, Robin R.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2015-05-14
- Volume
- 372
- Issue
- 20
- Pages
- 1887-1897
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4497809
- OpenAlex
- W265142245
- Semantic Scholar
- 31832b3aa3500171fc5f2a951f0a4124bd40068d
- Cited by
- 743
- References
- 29
- Citations by year
- 2026: 36 · 2025: 36 · 2024: 46 · 2023: 44 · 2022: 63 · 2021: 92 · 2020: 81 · 2019: 68 · 2018: 79 · 2017: 97 · 2016: 72 · 2015: 27
- FWCI
- 39.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Durham Research Online (Durham University) (acceptedVersion)
- Durham Research Online (Durham University) (submittedVersion, cc-by)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Research to Prevent Blindness
- Wellcome Trust
- Massachusetts Medical Society
- National Institute for Health and Care Research (NF-SI-0507-10204, NF-SI-0513-10074, NIHR-RP-011-003)
- Sir Jules Thorn Charitable Trust
- University College London
- European Commission
- Ulverscroft Foundation
- Durham University
- KU Leuven
- Moorfields Eye Hospital NHS Foundation Trust
- Directorate for Biological Sciences
- Medical Research Council (MR/K024000/1, MR/M015815/1, MR/J005215/1)
- Engineering and Physical Sciences Research Council (EP/J017698/1, EP/J005193/1)
- Biotechnology and Biological Sciences Research Council (BB/M00211X/1)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- Leber congenital amaurosis, RPE65, gene therapy, retinal degeneration, visual function, retinal sensitivity, electroretinogram, vector dose, intraocular inflammation, visual acuity, canine model, species differences, long-term efficacy and safety
- MeSH terms
- Retinoid Isomerohydrolase, Dependovirus, Adolescent, Animals, Child, Disease Models, Animal, Dogs, Genetic Vectors, Humans, Mutation, Retina, Vision, Ocular, Genetic Therapy, DNA, Complementary, Disease Progression, cis-trans-Isomerases, Photoreceptor Cells, Vertebrate, Young Adult, Leber Congenital Amaurosis
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