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

Abstract

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 (https://ichgcp.net/clinical-trials-registry/NCT03116113" title="See in ClinicalTrials.gov">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.

Conflict of interest statement

Competing Interest

R.E.M. scientific cofounder of Nightstar Therapeutics Inc. (now owned by Biogen Inc.); R.E.M., G.C.M.B. scientific advisors to the UK National Health Service National Institute for Health and Care Excellence (NICE) in relation to retinal gene therapy; M.D.F., B.L.L., B.J.L., R.E.M. consulting or on advisory board for Biogen Inc.; R.E.M., M.D.F. named inventors on the patent relating to codon-optimised RPGR gene therapy owned by the University of Oxford (US20180273594A1, originally filed 2015-09-10). M.D.F., G.C.M.B., R.E.M. scientific advisory board to Novartis; E.L., T.O., 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.

Figures

Fig. 1. Retinal sensitivity following gene therapy for X-linked retinitis pigmentosa in cohort 3 patients.

Mean retinal sensitivity (decibels, dB) and visual field, (represented by sensitivity heat maps) measured by microperimetry, showed progressive improvement in the treated eye from baseline to 6 months post-treatment. The untreated eye showed no change. Visual acuity, measured by ETDRS chart reading (number of letters), remained stable in both eyes. To minimize learning effects, baseline microperimetry was conducted in triplicate over a 2-day period at visit 1 for all subjects. The third reading was validated as an accurate baseline. At follow-up visits, assessments were conducted once for each eye, as per trial protocol.

Fig. 2. Transient regression of retinal function in the treated eye associated with subretinal inflammation at 5 weeks post high-dose gene therapy.

At week 5 post treatment with AAV8.coRPGR (6x1010 gp), patient C4.1 noticed some regression of vision in the treated eye following improvements over the preceding week. Microperimetry showed regression of retinal sensitivity and visual field (a), which was associated with subretinal lesions (white arrows) on optical coherence tomography (OCT) (b). Subretinal lesions (white arrows) could be seen to be scattered over the treated area of the macula on the OCT cross-sections (c-e), but spared the fovea (f); visual acuity was unaffected following treatment with a course of oral corticosteroids, the inflammation resolved with corresponding gains in retinal sensitivity recorded at 3 months follow-up.

Fig. 3. Outer nuclear layer changes following RPGR gene therapy.

(a) Full manual segmentation of 121-line scans of the OCT at three months of the central macula in the treated eye of patient C4.1 who received the high-dose AAV8.coRPGR vector. This shows increased thickness of the outer nuclear layer (ONL) compared with baseline. The 1, 3 and 6 mm ETDRS macula grid (right column) show mean sectoral ONL thickness changes (μm) and the heat map of ONL thickness (left column). The map shows an increase in retinal thickness (red) in a ring around the fovea of 10-15μm per quadrant, consistent with the OCT images both in terms of the magnitude and location of the retinal thickness change. (b) No change in retinal thickness was observed in the untreated eye. (c) Emergence of novel anatomical structures over areas of previously degenerate macula (red arrows) in the treated eye at 3 months following high-dose (6x1010 gp) RPGR gene therapy. This led to the OCT appearance of ‘double lines’, consisting of the new layer (red arrows) over the RPE layer (black layer). (d) No outer retinal changes were seen in the untreated eye. Scale bars = 200 μm.