Effect of gene therapy on visual function in Leber’s congenital amaurosis
Open accessAbstract
Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium-specific 65-kD protein (RPE65) is associated with poor vision at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clinically significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. We detected no change in retinal responses on electroretinography. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65. (ClinicalTrials.gov number, NCT00643747 [ClinicalTrials.gov].).
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Subretinal 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 [10]
The Summary (p. 1) describes subretinal AAV2/2-RPE65 treatment in three patients, with objective and subjective visual improvement in only one. The Patients and Study Design section (p. 2) reports follow-up of up to 12 months for one patient, so this paper does not establish sustained improvement in over 30 patients. (LLM, conf=0.89)
Experimental — accuracy not yet measuredAAV 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 [10]
The Summary (p. 1) describes an AAV gene-therapy trial in three young adults with RPE65-related Leber’s congenital amaurosis; one patient improved on measures of visual function, while none had a clinically significant change in visual acuity. The cited paper does not address clinical trials for hemophilia, familial lipoprotein lipase deficiency, or choroideremia, so it supports only the LCA part of the sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDespite a 28-day oral corticosteroid therapy started 2 days before the first IVT, 70.7% of lenadogene nolparvovec-treated eyes developed some degree of intraocular inflammation versus 10.2% of placebo-treated eyes.
“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&gt;A <i>MT-ND4</i> Leber optic neuropathy (2023) · cites this paper as [41]
Experimental — accuracy not yet measuredAAV 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 [10]
The techniques underpinning AAV-mediated retinal gene therapy have undergone iterative improvement since the first-in-human studies in RPE65-associated IRDs.
“The techniques underpinning AAV-mediated retinal gene therapy have undergone iterative improvement since the first-in-human studies in RPE65 -associated IRDs (Bainbridge et al., 2008; Hauswirth et al., 2008; Maguire et al., 2008).”
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., 2008
High numbers of rAAV particles (>10^12 vg) can give rise to transient inflammation in mice.
“Dose finding studies have shown that a high number of rAAV particles (>10 12 viral genomes (vg)) can give rise to transient inflammation in mice [35].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [35]
The Methods (p. 3) describe a human trial using vector at a concentration of 10^11 particles per milliliter. The Results (p. 3) report mild, self-limiting postoperative inflammation associated with vitrectomy, not high-dose vector exposure. Searches for mouse dose-finding studies and inflammation above 10^12 viral genomes found no passage addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredDirect injection into the subretinal space results in less exposure to plasma proteins, circulating antibodies, blood cells, and tissue-resident phagocytic cells.
“Direct injection into the subretinal space, as was the route for the first FDA-approved AAV vector, results in less exposure to plasma proteins, circulating antibodies, blood cells, and tissue-resident phagocytic cells [15].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [15]
Gene therapy gained its place in mainstream medical practice following FDA approval of Luxturna, an AAV2-based treatment for RPE65-LCA (LCA2).
“Gene therapy gained its place in mainstream medical practice following FDA approval of Luxturna, an AAV2- based treatment for the inherited retinal disease (IRD) retinal pigment epithelium (RPE)65-LCA (LCA2).”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [71]
In phase I/II clinical trials for RPE65-LCA at University College London, ocular inflammation was noted following SRI of 1 × 10^12 vg of AAV2-RPE65.
“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 [71]
Treated patients exhibited life-changing improvements in light sensitivity and visually guided behavior.
“Treated patients exhibited life-changing improvements in light sensitivity and visually guided behavior.”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [71]
CNS-directed AAV delivery has been associated with an increase in inflammatory mediators, including neutralizing antibodies, circulating CD45+ leukocytes, natural killer cells, and CD8+ and CD4+ T cells.
“CNS-directed AAV delivery has been associated with an increase in inflammatory mediators, including neutralizing antibodies, circulating CD45+ leukocytes, natural killer cells, and CD8+ and CD4+ T cells.13,14,15,16,17,18,19”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [13]
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- Authors
- Bainbridge, J. W. B., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G. E., Stockman, A., Tyler, N., Petersen-Jones, S., Bhattacharya, S. S., Thrasher, A. J., Fitzke, F. W., Carter, B. J., Rubin, G. S., Moore, A. T., & Ali, R. R.
- Affiliations
- Moorfields Eye Hospital (GB)
- University College London (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-05-22
- Volume
- 358
- Issue
- 21
- Pages
- 2231-2239
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2151809142
- Cited by
- 1,924
- References
- 25
- Citations by year
- 2026: 22 · 2025: 43 · 2024: 47 · 2023: 57 · 2022: 61 · 2021: 94 · 2020: 97 · 2019: 83 · 2018: 101 · 2017: 115 · 2016: 98 · 2015: 155 · 2014: 142 · 2013: 149 · 2012: 151
- FWCI
- 69.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research
- 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, gene therapy, subretinal injection, retinal dystrophy, visual function, microperimetry, visual acuity, electroretinogram
- MeSH terms
- Retinoid Isomerohydrolase, Dependovirus, Adolescent, Adult, Blindness, Carrier Proteins, Eye Proteins, Genetic Vectors, Humans, Injections, Mutation, Retina, Retinal Degeneration, Visual Acuity, Genetic Therapy, Gene Transfer Techniques, DNA, Complementary, cis-trans-Isomerases
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