The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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
“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
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
“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
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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 [12]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis
Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K. A., Testa, F., Surace, E. M., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802315 · Cited by 2,145
Self-citationEffect of gene therapy on visual function in Leber’s congenital amaurosis
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., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802268 · Cited by 1,924
Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1
Hacein-Bey-Abina, S., Garrigue, A., Wang, G. P., Soulier, J., Lim, A., Morillon, E., Clappier, E., Caccavelli, L., Delabesse, E., Beldjord, K., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35700 · Cited by 1,854
Howe, S. J., Mansour, M. R., Schwarzwaelder, K., Bartholomae, C., Hubank, M., Kempski, H., Brugman, M. H., Pike-Overzet, K., Chatters, S. J., de Ridder, D., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35798 · Cited by 1,286
PTC124 targets genetic disorders caused by nonsense mutations
Welch, E. M., Barton, E. R., Zhuo, J., Tomizawa, Y., Friesen, W. J., Trifillis, P., Paushkin, S. V., Patel, M., Trotta, C. R., Hwang, S., et al. (2007) · Nature · doi:10.1038/nature05756 · Cited by 1,175
Hauswirth, W. W., Aleman, T. S., Kaushal, S., Cideciyan, A. V., Schwartz, S. B., Wang, L., Conlon, T. J., Boye, S. L., Flotte, T. R., Byrne, B. J., et al. (2008) · Human Gene Therapy · doi:10.1089/hum.2008.107 · Cited by 954
Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle
Redmond., T. M., Yu, S., Lee, E., Bok, D., Hamasaki, D., Chen, N., Goletz, P., Ma, J.-X., Crouch, R. K., & Pfeifer, K. (1998) · Nature Genetics · doi:10.1038/3813 · Cited by 929
Self-citationLeber 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
Cideciyan, A. V., Alemán, T. S., Boye, S. L., Schwartz, S., Kaushal, S., Román, A. J., Pang, J., Sumaroka, A., Windsor, E. A. M., Wilson, J. M., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807027105 · Cited by 674
Self-citationAmplification and kinetics of the activation steps in phototransduction
Pugh, E. N., & Lamb, T. D. (1993) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(93)90038-h · Cited by 649
Simonelli, F., Maguire, A. M., Testa, F., Pierce, E. A., Mingozzi, F., Bennicelli, J. L., Rossi, S., Marshall, K. A., Banfi, S., Surace, E. M., et al. (2009) · Molecular Therapy · doi:10.1038/mt.2009.277 · Cited by 553
Self-citationRPE65 is the isomerohydrolase in the retinoid visual cycle
Moiseyev, G., Chen, Y., Takahashi, Y., Wu, B. X., & Ma, J.-X. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503460102 · Cited by 536
Acland, G. M., Aguirre, G. K., Bennett, J., Alemán, T. S., Cideciyan, A. V., Bennicelli, J. L., Dejneka, N. S., Pearce-Kelling, S. E., Maguire, A. M., Palczewski, K., et al. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2005.08.008 · Cited by 478
Self-citationRpe65 is the retinoid isomerase in bovine retinal pigment epithelium
Jin, M., Li, S., Moghrabi, W. N., Sun, H., & Travis, G. H. (2005) · Cell · doi:10.1016/j.cell.2005.06.042 · Cited by 424
Redmond, T. M., Poliakov, E., Yu, S., Tsai, J.-Y., Lu, Z., & Gentleman, S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504167102 · Cited by 409
Self-citationNatural Course of Retinitis Pigmentosa Over a Three-Year Interval
Berson, E. L., Sandberg, M. A., ROSNER, B. A., Birch, D. G., & Hanson, A. H. (1985) · American Journal of Ophthalmology · doi:10.1016/0002-9394(85)90351-4 · Cited by 323
Cideciyan, A. V., Hauswirth, W. W., Aleman, T. S., Kaushal, S., Schwartz, S. B., Boye, S. L., Windsor, E. A. M., Conlon, T. J., Sumaroka, A., Pang, J.-J., et al. (2009) · Human Gene Therapy · doi:10.1089/hum.2009.086 · Cited by 312
Jacobson, S. G., Alemán, T. S., Cideciyan, A. V., Sumaroka, A., Schwartz, S., Windsor, E. A. M., Traboulsi, E. I., Héon, E., Pittler, S. J., Milam, A. H., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500646102 · Cited by 276
Self-citationBennicelli, J., Wright, J. F., Komaromy, A., Jacobs, J. B., Hauck, B., Zelenaia, O., Mingozzi, F., Hui, D., Chung, D., Rex, T. S., et al. (2008) · Molecular Therapy · doi:10.1038/sj.mt.6300389 · Cited by 267
Self-citationVision 1 Year after Gene Therapy for Leber's Congenital Amaurosis
Cideciyan, A. V., Hauswirth, W. W., Alemán, T. S., Kaushal, S., Schwartz, S., Boye, S. L., Windsor, E. A. M., Conlon, T. J., Sumaroka, A., Román, A. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmc0903652 · Cited by 199
In Utero Gene Therapy Rescues Vision in a Murine Model of Congenital Blindness
Dejneka, N. S., Surace, E. M., Alemán, T. S., Cideciyan, A. V., Lyubarsky, A., Savchenko, A., Redmond, T. M., Tang, W., Wei, Z., Rex, T. S., et al. (2004) · Molecular Therapy · doi:10.1016/j.ymthe.2003.11.013 · Cited by 198
Self-citationEarly-onset severe rod-cone dystrophy in young children with RPE65 mutations.
Lorenz, B., Gyűrűs, P., Preising, M. N., Bremser, D., Gu, S., Andrassi-Darida, M., Gerth, C., & Gal, A. (2000) · PubMed · Cited by 194
Perrault, I., Rozet, J., Gerber, S., Ghazi, I., Leowski, C., Ducroq, D., Souied, E. H., Dufier, J., Münnich, A., & Kaplan, J. (1999) · Molecular Genetics and Metabolism · doi:10.1006/mgme.1999.2906 · Cited by 175
Latency of the Pupil Light Reflex: Sample Rate, Stimulus Intensity, and Variation in Normal Subjects
Bergamin, O., & Kardon, R. H. (2003) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.02-0468 · Cited by 157
National Cancer Institute (2020) · Definitions · doi:10.32388/j5tlqb · Cited by 153
Simonelli, F., Ziviello, C., Testa, F., Rossi, S., Fazzi, E. M., Bianchi, P. E., Fossarello, M., Signorini, S. G., Bertone, C., Galantuomo, M. S., et al. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-0068 · Cited by 144
Self-citationAlemán, T. S., Jacobson, S. G., Chico, J. D., Scott, M. L., Cheung, A. Y., Windsor, E. A. M., Furushima, M., Redmond, T. M., Bennett, J., Palczewski, K., et al. (2004) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.03-1230 · Cited by 101
Self-citationSeiple, W., Clemens, C. J., Greenstein, V. C., Carr, R. E., & Holopigian, K. (2004) · Documenta Ophthalmologica · doi:10.1007/s10633-005-0567-0 · Cited by 52
Jacobs, J. B., Dell’Osso, L. F., Hertle, R. W., Acland, G. M., & Bennett, J. (2006) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.05-1233 · Cited by 36
Self-citationJacobs, J. B., Dell’Osso, L., Hertle, R. W., et al. (2006) · Journal of American Association for Pediatric Ophthalmology and Strabismus · doi:10.1016/j.jaapos.2006.10.006 · Cited by 7
Research works printed but not linked: 1
- Lorenz, 2003, Early-onset severe rod-cone dystrophy in young children with RPE65 mutations, Invest Ophthalmol Vis Sci, 44, 1546
Cited by
Sorted by citations
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
Self-citationDunbar, C. E., High, K. A., Joung, J. K., Kohn, D. B., Ozawa, K., & Sadelain, M. (2018) · Science · doi:10.1126/science.aan4672 · Cited by 1,410
Self-citationImmune responses to AAV vectors: overcoming barriers to successful gene therapy
Mingozzi, F., & High, K. A. (2013) · Blood · doi:10.1182/blood-2013-01-306647 · Cited by 955
Self-citationHauswirth, W. W., Aleman, T. S., Kaushal, S., Cideciyan, A. V., Schwartz, S. B., Wang, L., Conlon, T. J., Boye, S. L., Flotte, T. R., Byrne, B. J., et al. (2008) · Human Gene Therapy · doi:10.1089/hum.2008.107 · Cited by 954
Gene therapy clinical trials worldwide to 2017: An update
Ginn, S. L., Amaya, A. K., Alexander, I. E., Edelstein, M., & Abedi, M. R. (2018) · The Journal of Gene Medicine · doi:10.1002/jgm.3015 · Cited by 903
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
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 ›
Are you an author, or do you see a problem with this page? Request a review
