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Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia
Open accessAbstract
Retinal gene therapy is increasingly recognized as a novel molecular intervention that has huge potential in treating common causes of blindness, the majority of which have a genetic aetiology1–5. Choroideremia is a chronic X-linked retinal degeneration that was first described in 18726. It leads to progressive blindness due to deficiency of Rab-escort protein 1 (REP1). We designed an adeno-associated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia. The primary endpoint was vision change in treated eyes 2 years after surgery compared to unoperated fellow eyes. Despite complications in two patients, visual acuity improved in the 14 treated eyes over controls (median 4.5 letter gain, versus 1.5 letter loss, P = 0.04), with 6 treated eyes gaining more than one line of vision (>5 letters). The results suggest that retinal gene therapy can sustain and improve visual acuity in a cohort of predominantly late-stage choroideremia patients in whom rapid visual acuity loss would ordinarily be predicted. The long-term follow-up results of a phase 1/2 retinal gene therapy clinical trial for choroideremia (NCT01461213) support the safety and efficacy of the treatment.
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“ocular AAV therapies leading to a permanent reduction in visual acuity following intraocular inflammation (9–11)”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [11]
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
“AAV dose-dependent intraocular inflammation and a few instances of persistent loss of visual acuity have been independently reported in clinical trials following subretinal AAV administration despite prophylactic immunosuppression (9–11).”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [11]
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
“Despite the perceived low immunogenicity of AAV and relative immune privilege of the intraocular environment,8 dose-dependent retinal inflammation, or gene therapy-associated uveitis (GTAU), has been observed in many retinal gene therapy trials, which limits the vector dose and therapeutic efficacy.”
From Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina (2021) · cites this paper as [6]
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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“In the phase 1/2 dose-escalation trials for RPE65-associated LCA, choroideremia, and retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa, patients receiving higher doses of AAV have presented with various signs of retinal inflammation, including vitritis, retinitis, and choroiditis,2,6,7 implicating the presence of a cell-mediated immune response.”
From Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina (2021) · cites this paper as [6]
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“Many current retinal gene therapy trials adopt a standardized immunosuppression protocol up to 21 days post-treatment, which may ameliorate this immune response in humans.6,7,40”
From Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina (2021) · cites this paper as [6]
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“In particular, the adoption of foot pedal-controlled viscous fluid injection systems has greatly improved injection pressure control during subretinal injection (Fischer et al., 2016; Xue et al., 2018).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Xue et al., 2018
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“In contrast, subretinal gene therapy appears to induce NAb formation only infrequently in clinical trials and pre-clinical studies (Rakoczy et al., 2015; Reichel et al., 2018; Xue et al., 2018; Fischer et al., 2020).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Xue et al., 2018
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“Although adeno-associated viral (AAV) vector-mediated retinal gene therapies have demonstrated efficacy”
From Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina (2021) · cites this paper as [6]
In the citing paper
“Nonetheless, inflammatory reactions to gene therapy in the eye have led to permanent vision loss for some patients7–9.”
From Investigation of Cas9 Antibodies in the Human Eye (2022) · cites this paper as [9]
In the citing paper
“A phase I/II clinical trial of subretinal gene therapy using an AAV2 vector to deliver human REP1 to the outer retina has shown sustained preservation or improvement of visual acuity over 2 to 5 years in patients with advanced disease [MacLaren 2014, Xue 2018].”
From Correcting visual loss by genetics and prosthetics (2020) · cites this paper as Xue 2018
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Citations
Cites
An analysis of variance test for normality (complete samples)
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Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis
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Self-citationRetinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase
Seabra, M. C., Brown, M. S., & Goldstein, J. L. (1993) · Science · doi:10.1126/science.8380507 · Cited by 337
Self-citationCloning of a gene that is rearranged in patients with choroideraemia
Cremers, F. P. M., van de Pol, D. J. R., van Kerkhoff, L. P. M., Wieringa, B., & Ropers, H.-H. (1990) · Nature · doi:10.1038/347674a0 · Cited by 333
A comprehensive review of retinal gene therapy
Boye, S. E., Boye, S. L., Lewin, A. S., & Hauswirth, W. W. (2013) · Molecular Therapy · doi:10.1038/mt.2012.280 · Cited by 262
Clinical Characteristics and Current Therapies for Inherited Retinal DegenerationsPreprint
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Ghazi, N. G., Abboud, E. B., Nowilaty, S. R., Alkuraya, H., Alhommadi, A., Cai, H., Hou, R., Deng, W.-T., Boye, S. L., Almaghamsi, A., et al. (2016) · Human Genetics · doi:10.1007/s00439-016-1637-y · Cited by 243
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Cited by
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AAV cis -regulatory sequences are correlated with ocular toxicity
Xiong, W., Wu, D. M., Xue, Y., Wang, S. K., Chung, M. J., Ji, X., Rana, P., Zhao, S. R., Mai, S., & Cepko, C. L. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1821000116 · Cited by 249
Bucher, K., Rodríguez-Bocanegra, E., Dauletbekov, D., & Fischer, M. D. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100915 · Cited by 242
Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses
Chan, Y. K., Wang, S. K., Chu, C. J., Copland, D. A., Letizia, A. J., Costa Verdera, H., Chiang, J. J., Sethi, M., Wang, M. K., Neidermyer, W. J., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abd3438 · Cited by 215
Garafalo, A. V., Cideciyan, A. V., Héon, E., Sheplock, R., Pearson, A., WeiYang Yu, C., Sumaroka, A., Aguirre, G. D., & Jacobson, S. G. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2019.100827 · Cited by 173
Fundus-controlled perimetry (microperimetry): Application as outcome measure in clinical trials
Pfau, M., Jolly, J. K., Wu, Z., Denniss, J., Lad, E. M., Guymer, R. H., Fleckenstein, M., Holz, F. G., & Schmitz-Valckenberg, S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100907 · Cited by 158
Self-citation
Metadata
- Authors
- Xue, K., Jolly, J. K., Barnard, A. R., Rudenko, A., Salvetti, A. P., Patrício, M. I., Edwards, T. L., Groppe, M., Orlans, H. O., Tolmachova, T., Black, G. C., Webster, A. R., Lotery, A. J., Holder, G. E., Downes, S. M., Seabra, M. C., & MacLaren, R. E.
- Affiliations
- University of Oxford (GB)
- Oxford University Hospitals NHS Trust (GB)
- Imperial College London (GB)
- St Mary's Hospital (GB)
- Moorfields Eye Hospital NHS Foundation Trust (GB)
- University of Southampton (GB)
- University College London (GB)
- Corresponding author
- MacLaren, Robert E.
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-10
- Volume
- 24
- Issue
- 10
- Pages
- 1507-1512
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC7032956
- OpenAlex
- W2893026352
- Semantic Scholar
- c5ea88dabcecb2c7d2fa7f60b4ea7a8e431e29d4
- Cited by
- 185
- References
- 36
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 21 · 2023: 17 · 2022: 23 · 2021: 40 · 2020: 34 · 2019: 26 · 2018: 1
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (091984)
- National Institute for Health and Care Research (NF-SI-0515-10020, HICF-1009-006, NF-SI-0515-10047, CL-2014-13-003, ICA-CDRF-2016-02-002)
- Royal College of Surgeons of Edinburgh
- University College London
- University of Oxford
- Oxford University Hospitals NHS Foundation Trust
- Moorfields Eye Hospital NHS Foundation Trust
- Medical Research Council (MR/N00101X/1)
- 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
- choroideremia, retinal gene therapy, Rab escort protein 1, REP1, adeno-associated virus vectors, subretinal injection, visual acuity, X-linked retinal degeneration, gene therapy clinical trials, visual outcome
- MeSH terms
- Dependovirus, Adult, Aged, Genetic Vectors, Humans, Male, Middle Aged, Retina, Retinal Degeneration, Vision, Ocular, Visual Acuity, Genetic Therapy, Choroideremia, Adaptor Proteins, Signal Transducing
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