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Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial
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Background Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis.Methods We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1.5 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) vector genomes) for up to 2 years.Findings AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477.Interpretation The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain.Funding Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.
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“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 [12]
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
“Induction of posterior vitreous detachment (PVD) is routinely performed as part of vitrectomy prior to subretinal vector administra tion but may be difficult in cases of strong adhesion. This may be important for the paediatric population, particularly as these patients stand to benefit most from retinal gene therapy (Maguire et al., 2009).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Maguire et al., 2009
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“Young patients are more likely to suffer given the higher cumulative doses of cortico steroids that will be required over a lifetime, yet are also the most likely to benefit from retinal gene therapy (Maguire et al., 2009).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Maguire et al., 2009
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“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”
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“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 [12]
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“Higher viral doses most commonly result in an increased antibody response [8, 16, 38], but several studies present contradicting results, with either no effect of viral dose, or a higher immune response to lower doses of AAV [39–41].”
From Characterization of anti-AAV2 neutralizing antibody levels in sheep prior to and following intravitreal AAV2.7m8 injection (2024) · cites this paper as [40]
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“Phase I to III clinical trials for Luxturna have consistently demonstrated its ability to bring about sustained improvements in low luminance vision in otherwise blind patients [Maguire 2009; Bennett 2016; Russell 2017].”
From Correcting visual loss by genetics and prosthetics (2020) · cites this paper as Maguire 2009
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Self-citation
Metadata
- Authors
- 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., Fulton, A., Marshall, K. A., Banfi, S., Chung, D. C., Morgan, J. I., Hauck, B., Zelenaia, O., Zhu, X., Raffini, L., Coppieters, F., De Baere, E., Shindler, K. S., Volpe, N. J., Surace, E. M., Acerra, C., Lyubarsky, A., Redmond, T. M., Stone, E., Sun, J., McDonnell, J. W., Leroy, B. P., Simonelli, F., & Bennett, J.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Boston Children's Hospital (US)
- National Institutes of Health (US)
- University of Iowa (US)
- ORCID
- Maguire, Albert M
- High, Katherine A
- Auricchio, Alberto
- Wright, J Fraser
- Pierce, Eric A
- Testa, Francesco
- Mingozzi, Federico
- Ying, Gui-shuang
- Rossi, Settimio
- Banfi, Sandro
- Chung, Daniel C
- Morgan, Jessica IW
- Zhu, Xiaosong
- Raffini, Leslie
- Coppieters, Frauke
- Shindler, Kenneth S
- Volpe, Nicholas J
- Surace, Enrico M
- Redmond, T Michael
- Stone, Edwin
- Sun, Junwei
- Leroy, Bart P
- Simonelli, Francesca
- Bennett, Jean
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 374
- Issue
- 9701
- Pages
- 1597-1605
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC4492302
- OpenAlex
- W2162290849
- Cited by
- 865
- References
- 30
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 38 · 2023: 33 · 2022: 34 · 2021: 46 · 2020: 50 · 2019: 31 · 2018: 47 · 2017: 64 · 2016: 49 · 2015: 77 · 2014: 71 · 2013: 58 · 2012: 76
- FWCI
- 30.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Eye Institute (U10EY013729, R01EY010820)
- National Center for Research Resources (UL1RR024134)
- 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, adeno-associated virus, subretinal injection, inherited retinal degeneration, visual function, pupillometry, electroretinogram, nystagmus, children, dose escalation, retinal pigment epithelium
- MeSH terms
- Retinoid Isomerohydrolase, Dependovirus, Adolescent, Adult, Age Factors, Blindness, Carrier Proteins, Child, Dark Adaptation, Dose-Response Relationship, Drug, Electroretinography, Eye Proteins, Female, Genetic Vectors, Humans, Injections, Male, Mutation, Nystagmus, Physiologic, Safety, Visual Acuity, Genetic Therapy, Treatment Outcome, Disease Progression, cis-trans-Isomerases, Optic Atrophy, Hereditary, Leber, Young Adult
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