Abstract

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 aetiology1,2,3,4,5. 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.

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Data availability

The authors declare that all of the data supporting the findings of this study are available within the paper and the Supplementary Information and are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all trial participants for their commitment to attending extensive follow-up visits, K. M. Jasani for helping with collection of the OCT and adverse events data, M. Hassall for helping with analysis of the AF data, and staff members of the Eye Research Group Oxford (ERGO) for their support throughout the study. This work was supported primarily by a grant (HICF-1009-006) from the Health Innovation Challenge Fund, a funding partnership between the UK Department of Health and the Wellcome Trust. Additional funding support was from the Health Foundation; Fight for Sight; the Lanvern Foundation; the Special Trustees of Moorfields Eye Hospital; the Royal College of Surgeons of Edinburgh and the National Institute for Health Research (NIHR) Biomedical Research Centres (BRC) at the Oxford University Hospitals NHS Foundation Trust (which includes the University of Oxford) and Moorfields Eye Hospital NHS Foundation Trust (which includes the University College London Institute of Ophthalmology).

Author information

Author notes

    • Graham E. Holder

    Present address: Department of Ophthalmology, National University of Singapore, Singapore, Singapore

Affiliations

  1. Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    • Kanmin Xue
    • , Jasleen K Jolly
    • , Alun R. Barnard
    • , Anna P. Salvetti
    • , Maria I. Patrício
    • , Thomas L. Edwards
    • , Markus Groppe
    • , Harry O. Orlans
    • , Susan M. Downes
    •  & Robert E. MacLaren
  2. Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    • Kanmin Xue
    • , Jasleen K Jolly
    • , Alun R. Barnard
    • , Anna Rudenko
    • , Anna P. Salvetti
    • , Maria I. Patrício
    • , Thomas L. Edwards
    • , Markus Groppe
    • , Harry O. Orlans
    • , Susan M. Downes
    •  & Robert E. MacLaren
  3. Molecular Medicine Section, National Heart and Lung Institute, Imperial College, London, UK

    • Tanya Tolmachova
  4. Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, Manchester Centre for Genomic Medicine, University Hospitals NHS Foundation Trust and Academic Health Sciences Centre, St Mary’s Hospital, Manchester, UK

    • Graeme C. Black
  5. Moorfields Eye Hospital NHS Foundation Trust, London, UK

    • Andrew R. Webster
    • , Graham E. Holder
    •  & Robert E. MacLaren
  6. University College London Institute of Ophthalmology, London, UK

    • Andrew R. Webster
    • , Graham E. Holder
    •  & Miguel C. Seabra
  7. Clinical Neurosciences Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

    • Andrew J. Lotery
  8. Chronic Diseases Research Centre, Nova Medical School, Universidade Nova de Lisboa, Lisbon, Portugal

    • Miguel C. Seabra

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Contributions

K.X., J.K.J., A.R.B., A.R., A.P.S., M.I.P. and T.L.E. collected the data and performed data analysis. K.X. and M.G. assisted with surgery. T.T., A.R.B., M.I.P. and H.O.O. tested the vector. G.C.B., A.R.W., A.J.L., S.M.D. and R.E.M. were clinical trial investigators, who designed the trial protocol, managed patient recruitment and interpreted the data. G.E.H. performed electrophysiology, data analysis and helped with trial design. R.E.M. and M.C.S. obtained funding and designed the study. R.E.M. and K.X. wrote the manuscript. All authors provided scientific input and read and approved the manuscript.

Competing interests

R.E.M.: scientific cofounder of Nightstar Therapeutics Inc.—a gene therapy company established by the University of Oxford and originally funded by the Wellcome Trust through Syncona Partners Ltd. A.R.B., G.C.B., A.J.L., G.C.B. and M.C.S.: consulting or on advisory board for Nightstar Therapeutics Inc. M.I.P., M.C.S. and R.E.M.: named inventors on patents relating to choroideremia gene therapy owned by the University of Oxford and Nightstar Therapeutics Inc. R.E.M., A.J.L. and G.C.B.: scientific advisory board to Spark Therapeutics Inc. The companies had no role in the conduct of this university-sponsored clinical trial, nor in the interpretation of the data, nor in the writing of the results. The views expressed are those of the authors and not necessarily those of the Wellcome Trust, the National Health Service, the NIHR or the UK Department of Health.

Corresponding author

Correspondence to Robert E. MacLaren.

Supplementary Information

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    Supplementary Figures 1–7, Supplementary Tables 1–7 and Supplementary Methods

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DOI

https://doi.org/10.1038/s41591-018-0185-5