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Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial
Open accessAbstract
Background Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study.Methods In this follow-on phase 1 trial, one dose of AAV2-hRPE65v2 (1.5 × 10(11) vector genomes) in a total volume of 300 μL was subretinally injected into the contralateral, previously uninjected, eyes of 11 children and adults (aged 11-46 years at second administration) with inherited retinal dystrophy caused by RPE65 mutations, 1.71-4.58 years after the initial subretinal injection. We assessed safety, immune response, retinal and visual function, functional vision, and activation of the visual cortex from baseline until 3 year follow-up, with observations ongoing. This study is registered with ClinicalTrials.gov, number NCT01208389.Findings No adverse events related to the AAV were reported, and those related to the procedure were mostly mild (dellen formation in three patients and cataracts in two). One patient developed bacterial endophthalmitis and was excluded from analyses. We noted improvements in efficacy outcomes in most patients without significant immunogenicity. Compared with baseline, pooled analysis of ten participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3 (mobility p=0.0003, white light full-field sensitivity p<0.0001), but no significant change was seen in the previously injected eyes over the same time period (mobility p=0.7398, white light full-field sensitivity p=0.6709). Changes in visual acuity from baseline to year 3 were not significant in pooled analysis in the second eyes or the previously injected eyes (p>0.49 for all time-points compared with baseline).Interpretation To our knowledge, AAV2-hRPE65v2 is the first successful gene therapy administered to the contralateral eye. The results highlight the use of several outcome measures and help to delineate the variables that contribute to maximal benefit from gene augmentation therapy in this disease.Funding Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Spark Therapeutics, US National Institutes of Health, Foundation Fighting Blindness, Institute for Translational Medicine and Therapeutics, Research to Prevent Blindness, Center for Advanced Retinal and Ocular Therapeutics, Mackall Foundation Trust, F M Kirby Foundation, and The Research Foundation-Flanders.
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“However, the presence of pre-existing neutralizing antibodies to AAV does not appear to correlate with a higher risk of retinal inflammation or reduced therapeutic efficacy, provided that the AAV vector is delivered via the subretinal route.27, 28, 29”
From Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina (2021) · cites this paper as [29]
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.
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“Apart from one participant who unfortunately devel oped culture-positive bacterial endophthalmitis after surgery, no par ticipants demonstrated intraocular inflammation or CRA within three years of second eye treatment.”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bennett et al., 2016
Experimental — accuracy not yet measuredIn the citing paper
“Furthermore, in the clinical setting, ocular and intrathecal AAV gene delivery have shown limited transgene-related immune responses, possibly due to their compartmentation and reduced antigen presentation [16, 132, 133].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [133]
In 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 Bennett 2016
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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
Gene therapy restores vision in a canine model of childhood blindness
Acland, G. M., Aguirre, G. D., Ray, J., Zhang, Q., Aleman, T. S., Cideciyan, A. V., Pearce-Kelling, S. E., Anand, V., Zeng, Y., Maguire, A. M., et al. (2001) · Nature Genetics · doi:10.1038/ng0501-92 · Cited by 1,202
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
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
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Self-citationLong-Term Effect of Gene Therapy on Leber’s Congenital Amaurosis
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Jacobson, S. G. (2012) · Archives of Ophthalmology · doi:10.1001/archophthalmol.2011.298 · Cited by 639
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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-citationChan, K. Y., Jang, M. J., Yoo, B. B., Greenbaum, A., Ravi, N., Wu, W.-L., Sánchez-Guardado, L., Lois, C., Mazmanian, S. K., Deverman, B. E., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4593 · Cited by 1,578
Dunbar, 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-citationThe current landscape of nucleic acid therapeutics
Kulkarni, J. A., Witzigmann, D., Thomson, S. B., Chen, S., Leavitt, B. R., Cullis, P. R., & van der Meel, R. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00898-0 · Cited by 1,371
Adeno-Associated Virus (AAV) as a Vector for Gene Therapy
Naso, M. F., Tomkowicz, B., Perry, W. L., & Strohl, W. R. (2017) · BioDrugs · doi:10.1007/s40259-017-0234-5 · Cited by 1,362
Metadata
- Authors
- Bennett, J., Wellman, J., Marshall, K. A., McCague, S., Ashtari, M., DiStefano-Pappas, J., Elci, O. U., Chung, D. C., Sun, J., Wright, J. F., Cross, D. R., Aravand, P., Cyckowski, L. L., Bennicelli, J. L., Mingozzi, F., Auricchio, A., Pierce, E. A., Ruggiero, J., Leroy, B. P., Simonelli, F., High, K. A., & Maguire, A. M.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Spark Therapeutics (United States) (US)
- University of Pennsylvania (US)
- Federico II University Hospital (IT)
- Massachusetts Eye and Ear Infirmary (US)
- University of Campania "Luigi Vanvitelli" (IT)
- Corresponding author
- Bennett, Jean
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 388
- Issue
- 10045
- Pages
- 661-672
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC5351775
- OpenAlex
- W2473832992
- Cited by
- 461
- References
- 29
- Citations by year
- 2026: 28 · 2025: 32 · 2024: 31 · 2023: 41 · 2022: 50 · 2021: 54 · 2020: 66 · 2019: 38 · 2018: 55 · 2017: 56 · 2016: 8
- FWCI
- 27.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- FWO Flanders (grant OZP 3G004306)
- 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
- RPE65 mutations, inherited retinal disease, subretinal gene therapy, recombinant adeno-associated virus vectors, immune response, visual function, mobility, visual cortex activation, pediatric patients
- MeSH terms
- Retinoid Isomerohydrolase, Dependovirus, Adolescent, Adult, Blindness, Child, Female, Follow-Up Studies, Genetic Vectors, Humans, Male, Middle Aged, Mutation, Occipital Lobe, Vision, Ocular, Genetic Therapy, Linear Models, Age of Onset, Retinal Rod Photoreceptor Cells, Retinal Cone Photoreceptor Cells, Retreatment, Evidence-Based Medicine, cis-trans-Isomerases, Injections, Intraocular, Administration, Ophthalmic, Patient Safety
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