Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years
Open accessAbstract
OBJECTIVE: To determine the safety and efficacy of subretinal gene therapy in the RPE65 form of Leber congenital amaurosis using recombinant adeno-associated virus 2 (rAAV2) carrying the RPE65 gene. DESIGN: Open-label, dose-escalation phase I study of 15 patients (range, 11-30 years of age) evaluated after subretinal injection of the rAAV2- RPE65 vector into the worse-functioning eye. Five cohorts represented 4 dose levels and 2 different injection strategies. MAIN OUTCOME MEASURES: Primary outcomes were systemic and ocular safety. Secondary outcomes assayed visual function with dark-adapted full-field sensitivity testing and visual acuity with Early Treatment Diabetic Retinopathy Study charts. Further assays included immune responses to the vector, static visual fields, pupillometry, mobility performance, and optical coherence tomography. RESULTS: No systemic toxicity was detected; ocular adverse events were related to surgery. Visual function improved in all patients to different degrees; improvements were localized to treated areas. Cone and rod sensitivities increased significantly in the study eyes but not in the control eyes. Minor acuity improvements were recorded in many study and control eyes. Major acuity improvements occurred in study eyes with the lowest entry acuities and parafoveal fixation loci treated with subretinal injections. Other patients with better foveal structure lost retinal thickness and acuity after subfoveal injections. CONCLUSIONS: Gene therapy for Leber congenital amaurosis caused by RPE65 mutations is sufficiently safe and substantially efficacious in the extrafoveal retina. There is no benefit and some risk in treating the fovea. No evidence of age-dependent effects was found. Our results point to specific treatment strategies for subsequent phases. APPLICATION TO CLINICAL PRACTICE: Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00481546.
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Ochacovski et al showed that subretinal injection in non-human primates can cause mild thinning of the outer layers of the fovea in comparison with an intravitreal injection of the same vector.
“Ochacovski et al89 have shown that subretinal injection, in NHPs, can cause mild thinning of the outer layers of the fovea in comparison with an intravitreal injection of the same vector.89,90”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [89]
The Results (Visual Acuity, Fixation and Foveal Optical Coherence Tomography; page not provided) report foveal thinning in some patients after subretinal injection. The paper studies humans with RPE65-related disease, however; it does not report an Ochacovski study in non-human primates or compare subretinal with intravitreal injection of the same vector. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWild-type AAV-based gene therapies for ophthalmologic indications generally require relatively high doses and/or administration via subretinal injection, an invasive surgical procedure that requires detachment of photoreceptors from the RPE and reportedly results in transduction of less than 5% of the retinal surface.
“As a consequence, wild-type AAV-based gene therapies for ophthalmologic indications generally require relatively high doses and/or administration via subretinal injection, an invasive surgical procedure that requires detachment of photoreceptors from the RPE and reportedly results in transduction of <5% of the retinal surface. 25 – 27”
From Design and Characterization of a Novel Intravitreal Dual-Transgene Genetic Medicine for Neovascular Retinopathies (2024) · cites this paper as [25]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSubretinal AAV2 RPE65 trials in LCA showed sustained improvement in subjective and objective vision in over 30 patients.
“during Phase I/II clinical trials for Leber's congenital amaurosis (LCA), over 30 patients who received a subretinal injection of AAV2 encoding RPE65, an enzyme responsible for the isomerohydrolase activity of retinal pigment epithelium, showed sustained improvement in both subjective and objective measurements of vision.8–14”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [14]
The Design passage describes subretinal AAV2-RPE65 treatment in 15 patients, and the Comment reports improved visual function on full-field stimulus testing in all 15, with follow-up extending to three years for the initial cohort. This paper does not establish sustained improvement in both subjective and objective vision measures in over 30 patients; its Results also caution that most visual-acuity changes were not clinically significant. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIncreasing the total dose delivered to the eye but dividing AAV particles across more than one subretinal bleb appears to have little impact on the intraocular and systemic immune response compared to if the viral particles were concentrated within a single bleb.
“Based on the results from small cohort studies, increasing the total dose delivered to the eye but dividing AAV particles across more than one subretinal bleb appears to have little impact on the intraocular and systemic immune response compared to if the viral particles were concentrated within a single bleb (Jacobson et al., 2012; Ghazi et al., 2016; Weleber et al., 2016; Le Meur et al.”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Jacobson et al., 2012
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredBleb fusion may lead to retinal detachment and additional surgery.
“However, caution to avoid bleb fusion is required as this may lead to retinal detachment and additional surgery (Jacobson et al., 2012).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Jacobson et al., 2012
The Results (Study Population, Adverse Events and Complications; page unavailable) report that P7 developed a postoperative retinal detachment near the subretinal injection site and required surgical repair. The paper does not identify bleb fusion as the cause or say that avoiding bleb fusion would prevent this complication. (LLM, conf=0.86)
Experimental — accuracy not yet measured
AAV clinical successes to date have involved delivery either to immune privileged regions or to subjects lacking apparent AAV immunological memory.
“As a result, AAV clinical successes to date have involved delivery either to immune privileged regions or to subjects lacking apparent AAV immunological memory.8–14,30,42”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [14]
AAV has been successful in clinical gene therapy trials for LCA, hemophilia, familial lipoprotein lipase deficiency, and choroideremia.
“Adeno-associated virus has been successful in clinical gene therapy trials for Leber's congenital amaurosis, hemophilia, familial lipoprotein lipase deficiency, and choroideremia.8–15,26,27,60,61”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [14]
The difference in foveal thinning between subretinal and intravitreal injection in non-human primates was not clinically significant.
“However, the difference was not clinically significant.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [89]
The Results section on foveal optical coherence tomography reports thinning in human patients after subretinal injection, and the Comment section discusses its possible clinical implications. Searches for non-human primates and intravitreal injection found no passage comparing the two injection routes or assessing whether a difference in foveal thinning was clinically significant. The paper's statement about clinical significance concerns visual-acuity improvement, not that comparison; page numbers were unavailable. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIVT delivery of therapeutic transgenes to multiple cell types across the entire retina has not been feasible with wild-type AAV vectors owing in part to their limited capacity to efficiently transit the vitreous and penetrate the inner limiting membrane and superficial ganglion cell layer.
“however, IVT delivery of therapeutic transgenes to multiple cell types across the entire retina has not been feasible with wild-type AAV vectors owing in part to their limited capacity to efficiently transit the vitreous and penetrate the inner limiting membrane (ILM) and superficial ganglion cell layer. 25”
From Design and Characterization of a Novel Intravitreal Dual-Transgene Genetic Medicine for Neovascular Retinopathies (2024) · cites this paper as [25]
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn silico modeling showed that the 10-amino-acid peptide insertion at position R588 disrupts binding to heparan sulfate.
“Investigation of R100 structure–function relationships through in silico modeling showed that the 10-amino-acid peptide insertion at position R588 disrupts binding to heparan sulfate, an abundant proteoglycan in the ILM. 25”
From Design and Characterization of a Novel Intravitreal Dual-Transgene Genetic Medicine for Neovascular Retinopathies (2024) · cites this paper as [25]
The Results—Immune Response Assays section discusses AAV2 capsid immune responses, not structural modeling or heparan-sulfate binding. Searches for R588, the 10-amino-acid insertion, R100, and in silico modeling found no passage addressing the claim. Page numbers are unavailable in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIn one clinical trial with patients who presented with pre-existing antibodies against AAV2, subretinal injection of AAV2-mediated gene therapy caused only four of 15 subjects to experience a significant increase of circulating anti-AAV2 antibodies in serum, suggesting a limited systemic response.
“In one clinical trial with patients who presented with pre-existing antibodies against AAV2, subretinal injection of AAV2-mediated gene therapy caused only four of 15 subjects to experience a significant increase of circulating anti-AAV2 antibodies in serum, suggesting a limited systemic response (Jacobson et al., 2012).”
From AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery (2023) · cites this paper as Jacobson et al., 2012
SRI of vector under the fovea of some LCA2 patients led to central retinal thinning and loss of visual acuity.
“SRI of vector under the fovea of some LCA2 patients led to central retinal thinning and loss of visual acuity.75”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [75]
The requirement for vitrectomy and transvitreal approaches can cause complications such as cataracts and retinal tear formation/detachment.
“the requirement for vitrectomy and transvitreal approaches can cause complications such as cataracts and retinal tear formation/detachment [292,293,294].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [294]
Subfoveal viral gene therapy has been associated with various adverse effects, such as RPE alterations, retinal thinning, foveal morphological changes, vision loss, and variable duration of clinical effects.
“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 [294]
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“Moreover, several adverse effects, including foveal thinning, macular holes, choroidal effusion, and ocular hypo- or hypertension have been observed during the immediate postoperative days.(2,3,8,9) Consequently, subretinal injection can potentially lead to permanent visual dysfunction.”
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AAV-mediated RLBP1 gene therapy improves the rate of dark adaptation in Rlbp1 knockout mice
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“…AAV particles across more than one subretinal bleb appears to have little impact on the intraocular and systemic immune response compared to if the viral particles were concentrated within a single bleb (Jacobson et al., 2012; Ghazi et al., 2016; Weleber et al., 2016; Le Meur et al., 2018).”
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- Authors
- Jacobson, S. G.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Jacobson, Samuel G.
- ORCID
- Jacobson, Samuel G.
- Venue
- Archives of Ophthalmology
- Publisher
- American Medical Association (AMA)
- Published
- 2012-01-01
- Volume
- 130
- Issue
- 1
- Pages
- 9
- ISSN
- 0003-9950 (ISSN-L)
- PMC
- PMC3600816
- OpenAlex
- W2152853777
- Cited by
- 639
- References
- 54
- Citations by year
- 2026: 17 · 2025: 24 · 2024: 25 · 2023: 28 · 2022: 25 · 2021: 49 · 2020: 36 · 2019: 42 · 2018: 46 · 2017: 49 · 2016: 55 · 2015: 74 · 2014: 68 · 2013: 53 · 2012: 44
- FWCI
- 21.40
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Archives of Ophthalmology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (P30EY021721, U10EY017280)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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 mutations, subretinal gene therapy, recombinant adeno-associated virus 2, inherited retinal disease, visual function, visual acuity, dose escalation
- MeSH terms
- Retinoid Isomerohydrolase, Dependovirus, Adolescent, Adult, Carrier Proteins, Child, Eye Proteins, Female, Follow-Up Studies, Genetic Vectors, Humans, Male, Mutation, Photic Stimulation, Psychomotor Performance, Pupil, Visual Acuity, Visual Fields, Genetic Therapy, Treatment Outcome, cis-trans-Isomerases, Photoreceptor Cells, Vertebrate, Tomography, Optical Coherence, Young Adult, Injections, Intraocular, Leber Congenital Amaurosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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