Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR


Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in 18 patients over up to 6 months of follow-up ( NCT03116113). The primary outcome of the study was safety, and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no notable safety concerns after subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8-coRPGR), meeting the pre-specified primary endpoint. Visual field improvements beginning at 1 month and maintained to the last point of follow-up were observed in six patients.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Retinal sensitivity after gene therapy for X-linked RP in C3 patients.
Fig. 2: Transient regression of retinal function in the treated eye associated with subretinal inflammation at 5 weeks after high-dose gene therapy.
Fig. 3: ONL changes after RPGR gene therapy.

Data availability

All requests for raw and analyzed data and materials are promptly reviewed by the Nuffield Laboratory of Ophthalmology, Oxford University and the sponsor, Biogen Inc., to verify whether the request is subject to any intellectual property or confidentiality obligations. Patient-related data not included in the paper were generated as part of the clinical trials and may be subject to patient confidentiality. Any data and materials that can be shared will be released via a material transfer agreement upon reasonable request.


  1. 1.

    Talib, M. et al. Clinical and genetic characteristics of male patients with RPGR-associated retinal dystrophies: a long-term follow-up study. Retina 39, 1186–1199 (2018).

    Article  Google Scholar 

  2. 2.

    Bennett, J. Taking stock of retinal gene therapy: looking back and moving forward. Mol. Ther. 25, 1076–1094 (2017).

    CAS  Article  Google Scholar 

  3. 3.

    Vandenberghe, L. H. What is next for retinal gene therapy? Cold Spring Harb. Perspect. Med. 5, a017442 (2015).

    Article  Google Scholar 

  4. 4.

    Boye, S. E., Boye, S. L., Lewin, A. S. & Hauswirth, W. W. A comprehensive review of retinal gene therapy. Mol. Ther. 21, 509–519 (2013).

    CAS  Article  Google Scholar 

  5. 5.

    Sahel, J. A., Marazova, K. & Audo, I. Clinical characteristics and current therapies for inherited retinal degenerations. Cold Spring Harb. Perspect. Med. 5, a017111 (2014).

    Article  Google Scholar 

  6. 6.

    Duncan, J. L. et al. Inherited retinal degenerations: current landscape and knowledge gaps. Transl. Vis. Sci. Technol. 7, 6 (2018).

    Article  Google Scholar 

  7. 7.

    DiCarlo, J. E., Mahajan, V. B. & Tsang, S. H. Gene therapy and genome surgery in the retina. J. Clin. Invest. 128, 2177–2188 (2018).

    Article  Google Scholar 

  8. 8.

    Baker, C. K. & Flannery, J. G. Innovative optogenetic strategies for vision restoration. Front. Cell Neurosci. 12, 316 (2018).

    CAS  Article  Google Scholar 

  9. 9.

    Megaw, R. D., Soares, D. C. & Wright, A. F. RPGR: its role in photoreceptor physiology, human disease, and future therapies. Exp. Eye Res. 138, 32–41 (2015).

    CAS  Article  Google Scholar 

  10. 10.

    Russell, S. et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 390, 849–860 (2017).

    CAS  Article  Google Scholar 

  11. 11.

    Deng, W.-T. et al. Stability and safety of an AAV vector for treating RPGR-ORF15X-linked retinitis pigmentosa. Hum. Gene Ther. 26, 593–602 (2015).

    CAS  Article  Google Scholar 

  12. 12.

    Wu, Z. et al. A long-term efficacy study of gene replacement therapy for RPGR-associated retinal degeneration. Hum. Mol. Genet. 24, 3956–3970 (2015).

    CAS  Article  Google Scholar 

  13. 13.

    Pawlyk, B. S. et al. Photoreceptor rescue by an abbreviated human RPGR gene in a murine model of X-linked retinitis pigmentosa. Gene Ther. 23, 196–204 (2015).

    Article  Google Scholar 

  14. 14.

    Sun, X. et al. Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations. Proc. Natl Acad. Sci. USA 113, E2925–E2934 (2016).

    CAS  Article  Google Scholar 

  15. 15.

    Fischer, M. D. et al. Codon-optimized RPGR improves stability and efficacy of AAV8 gene therapy in two mouse models of X-linked retinitis pigmentosa. Mol. Ther. 25, 1854–1865 (2017).

    CAS  Article  Google Scholar 

  16. 16.

    Xue, K., Groppe, M., Salvetti, A. P. & MacLaren, R. E. Technique of retinal gene therapy: delivery of viral vector into the subretinal space. Eye 31, 1308–1316 (2017).

    CAS  Article  Google Scholar 

  17. 17.

    Maguire, A. M. et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. NEJM 358, 2240–2248 (2008).

    CAS  Article  Google Scholar 

  18. 18.

    Cukras, C. et al. Retinal AAV8-RS1 gene therapy for X-linked retinoschisis: initial findings from a phase I/IIa trial by intravitreal delivery. Mol. Ther. 26, 2282–2294 (2018).

    CAS  Article  Google Scholar 

  19. 19.

    Hood, D. C., Lazow, M. A., Locke, K. G., Greenstein, V. C. & Birch, D. G. The transition zone between healthy and diseased retina in patients with retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 52, 101–108 (2011).

    Article  Google Scholar 

  20. 20.

    Tee, J. J. L., Carroll, J., Webster, A. R. & Michaelides, M. Quantitative analysis of retinal structure using spectral-domain optical coherence tomography in RPGR-associated retinopathy. Am. J. Ophthalmol. 178, 18–26 (2017).

    Article  Google Scholar 

  21. 21.

    Birch, D. G. et al. Rates of decline in regions of the visual field defined by frequency-domain optical coherence tomography in patients with RPGR-mediated X-linked retinitis pigmentosa. Ophthalmology 122, 833–839 (2015).

    Article  Google Scholar 

  22. 22.

    Tang, P. H., Jauregui, R., Tsang, S. H., Bassuk, A. G. & Mahajan, V. B. Optical coherence tomography angiography of RPGR-associated retinitis pigmentosa suggests foveal avascular zone is a biomarker for vision loss. Ophthal. Surg. Lasers Imaging Retina 50, e44–e48 (2019).

    Article  Google Scholar 

  23. 23.

    Duncan, J. L. et al. High-resolution imaging with adaptive optics in patients with inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci. 48, 3283–3291 (2007).

    Article  Google Scholar 

  24. 24.

    Cideciyan, A. V. et al. Progression in X-linked retinitis pigmentosa due to ORF15-RPGR mutations: assessment of localized vision changes over 2 years. Invest. Ophthalmol. Vis. Sci. 59, 4558–4566 (2018).

    CAS  Article  Google Scholar 

  25. 25.

    Bennett, J. et al. 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. Lancet 388, 661–672 (2016).

    CAS  Article  Google Scholar 

  26. 26.

    Storer, B. E. Design and analysis of phase I clinical trials. Biometrics 45, 925–937 (1989).

    CAS  Article  Google Scholar 

  27. 27.

    Klein, R., Klein, B. E., Moss, S. E. & DeMets, D. Inter-observer variation in refraction and visual acuity measurement using a standardized protocol. Ophthalmology 90, 1357–1359 (1983).

    CAS  Article  Google Scholar 

  28. 28.

    MacLaren, R. E. et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 383, 1129–1137 (2014).

    CAS  Article  Google Scholar 

Download references


We thank all trial participants for their commitment to the trial and for attending their follow-up visits, and staff members of the Eye Research Group Oxford for their support throughout the study. The trial was sponsored by Nightstar Therapeutics, now Biogen Inc. ( NCT03116113), with additional research infrastructure support provided by the National Institute for Health Research (NIHR), Oxford Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health. We thank B. Lujan, Medical Director of the Casey Eye Institute Reading Center, Portland, OR, USA and the Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, CA, USA, both of which independently reviewed and verified the findings from the SD-OCT data.

Author information




J.C.-K., K.X., A.N., A.D., L.J.W., A.P.S., J.K.J., G.C.M.B., N.Z.G., J.L.D., P.R.R., A.J.L., B.L.L., P.E.S. and R.E.M. recruited and monitored trial participants during screening and follow-up visits. R.E.M., P.E.S. and J.L.D. performed the gene therapy surgery. J.C.-K., K.X. and N.Z.G. assisted with the gene therapy surgery. J.C.-K., K.X., E.L., J.W.A., B.J.L., T.O., A.G., G.C.M.B. and R.E.M. collected data and performed the data analysis. C.M.-F.d.I.C., M.D.F. and R.E.M. performed preclinical studies to validate the vector. A.R.B. was the biological safety officer. A.G., T.O. and R.E.M. designed the trial protocol. J.C.-K., K.X. and R.E.M. wrote and revised the manuscript. All the authors provided scientific input, and read and approved the manuscript.

Corresponding author

Correspondence to Robert E. MacLaren.

Ethics declarations

Competing interests

R.E.M. is the scientific cofounder of Nightstar Therapeutics Inc. (now owned by Biogen Inc.). R.E.M. and G.C.M.B. are scientific advisors to the UK’s National Institute for Health and Care Excellence in relation to retinal gene therapy. M.D.F., B.L.L., B.J.L. and R.E.M. are consultants or on the advisory board for Biogen Inc. R.E.M. and M.D.F. are the named inventors on the patent relating to codon-optimized RPGR gene therapy, owned by the University of Oxford (patent no. US20180273594A1, originally filed 10 September 2015). M.D.F., G.C.M.B. and R.E.M. are on the scientific advisory board to Novartis. E.L., T.O. and A.G. were employees of the sponsor of the trial, Nightstar Therapeutics (now Biogen Inc.). The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the UK Department of Health.

Additional information

Peer review information K. Gao was the primary editor on this article, and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Immunohistochemical analysis of human RPGR expression in Rpgr-/- mouse retinae following subretinal injection of 7.5 × 109 gp of AAV8.RK.coRPGR.

Representative confocal images from cryosections of the treated eye 1-month post-subretinal vector injection versus the untreated eye of one mouse of one of the four independent experiments performed. Nuclear labeling with Hoechst (blue), together with Nomarski interference contrast, shows good preservation of retinal layers in both eyes. Human RPGR protein (hRPGR, green) staining was selectively detected in the region of the photoreceptor connecting cilia (CC) in the treated retina but not in the untreated retina. In the treated retina, hRPGR could also be seen to co-localize with native mouse RPGRIP1 (red), which is known to tether RPGR to the connecting cilia. In addition, hRPGR partially co-localizes with antibody staining for glutamylated proteins (GT335) at the connecting cilia, with the more distal non-colocalizing GT335 staining likely to represent glutamylated tubulin. ONL, outer nuclear layer; IS, inner segment; OS, outer segment; RPE, retinal pigment epithelium. Scale bar = 5 μm.

Extended Data Fig. 2 Site of subretinal bleb/s post gene therapy in all 18 trial participants.

The bleb sites are marked with red circles, showing the extent of retinal detachment for subretinal gene delivery. The retinotomy sites are marked with X.

Extended Data Fig. 3 Dose-response plots following retinal gene therapy for X-linked retinitis pigmentosa in trial participants.

Retinal sensitivity derived from microperimetry measurements is represented as percentage change from baseline at 1, 3 and 6 months for treated and untreated eyes in 6 cohorts of patients receiving increasing concentrations of AAV8.coRPGR vector (from 5 × 1010 gp/ml to 5 × 1012 gp/ml). Data are not available for subjects C2.2 and C2.3 (lack of triplicate assessments at baseline) and C4.3 (untreated eye at month 6 due to incorrect test setting).

Extended Data Fig. 4 Quantification of individual microperimetry points shows sustained treatment effect post-gene therapy up to at least 6 months of follow-up in cohort 3 patients.

The total number of microperimetry loci with increased retinal sensitivity (>1 dB up to >7 dB) in all cohort 3 patients seen at month one was sustained to at least month 6 follow-up. The distribution of the points across the different sensitivities is non-parametric. As expected, due to variability, a number of points in the untreated eyes showed increases of >1 dB from baseline. At higher thresholds however the increases were seen disproportionately in the treated eyes and notably, a >7 dB gain was seen only in loci in the treated eyes by 6 months. Note—the figure shows the total number of points across all eyes and not the mean per eye.

Extended Data Fig. 5 Scatter plots for secondary endpoints: Visual acuity (BCVA, ETRS letters), microperimetry (dB) and SD-OCT (central retinal thickness) showing mean values with 95% confidence intervals at baseline and 6 months post retinal gene therapy.

BCVA remained stable at 6 months follow-up compared to baseline in both treated and untreated eyes. Treated eyes (n = 18): baseline mean 57.2 letters; mean at 6 months 57.1, mean change at 6 months −0.1 letters (95% CI −2.8 to 2.6). Untreated eyes (n = 18): baseline mean 65.9 letters; mean at 6 months 66.7 letters; mean change at 6 months +0.8 letters (95% CI −1.3 to 2.9). Mean microperimetry remained stable at 6 months follow-up compared to baseline in both treated and untreated eyes. Treated eyes (n = 18): baseline mean 3.2 dB, mean at 6 months 3.6 dB; mean change at 6 months + 0.5 dB (95% CI −0.7 to 1.7). Untreated eyes (n = 18): baseline mean 3.7 dB, mean at 6 months 3.7 dB; mean change at 6 months +0.1 dB (95% CI −0.5 to 0.7). Mean central retinal thickness remained stable at 6 months follow-up compared to baseline in both treated and untreated eyes. Treated eyes (n = 18): baseline mean 143.6 µm, mean at 6 months 132.7 µm; mean change at 6 months −10.8 µm (95% CI −25.1 to 3.5). Untreated eyes (n = 18): baseline mean 162.2 µm, mean at 6 months 151.3 µm; mean change at 6 months -10.9 µm (95% CI −19.8 to −2.1).

Extended Data Fig. 6 Outer nuclear layer changes following RPGR gene therapy with the lowest dose vector.

Full segmentation of 121-line scans of the OCT showed no change in thickness of the outer nuclear layer (ONL) over the central macula in the treated eye of patient C1.2 who received a low-dose (5 × 109 gp) AAV8.coRPGR vector. The 1, 3 and 6 mm ETDRS circles (left column) and heat maps (right column) show changes in mean sectoral ONL thickness (μm) in the treated (a) and untreated (b) eyes. No appreciable change in ONL thickness was observed in either eye. No structural changes in outer retinal layers were observed on OCT cross-sections in the treated (c) and untreated (d) eyes at 3 months compared with baseline. Scale bars = 200 μm.

Supplementary information

Supplementary Information

Supplementary methods, Tables 1–5, Figs. 1–3 and references.

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cehajic-Kapetanovic, J., Xue, K., Martinez-Fernandez de la Camara, C. et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Nat Med 26, 354–359 (2020).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing