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 1 , 2 , 3 , 4 , 5 , 6 . Here we report the first in human Phase I/II dose escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene 7 in 18 patients up to 6 months follow-up ( 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 significant safety concerns following subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8. coRPGR ) 8 meeting the pre-specified primary endpoint. Visual field improvements beginning at one month and maintained to the last point of follow-up were observed in six patients.

Inherited retinal degenerations are the leading cause of blindness in the working population. X-linked retinitis pigmentosa (XLRP), caused by mutations in the Retinitis pigmentosa GTPase regulator (RPGR) gene is one of the more severe forms, and female carriers of RPGR mutations have a variable presentation. A retrospective review of twenty-three female RPGR carriers aged between 8 and 76 years old was carried out using fundoscopy, autofluorescence imaging (AF), blue reflectance (BR) imaging and optical coherence tomography (OCT). Confirmation of the genetic mutation was obtained from male relatives or Sanger genetic sequencing. Fundus examination and AF demonstrate phenotypic variability in RPGR carriers. The genetic mutation appears indeterminate of the degree of change. We found four distinct classifications based on AF images to describe RPGR carriers; normal (N) representing normal or near-normal AF appearance (n = 1, 4%); radial (R) pattern reflex without pigmentary retinopathy (n = 14, 61%); focal (F) pigmentary retinopathy (n = 5, 22%) and; male (M) phenotype (n = 3, 13%). The phenotypes were precisely correlated in both eyes (rs = 1.0, p < 0.0001). Skewed X-inactivation can result in severely affected carrier females—in some cases indistinguishable from the male pattern and these patients should be considered for RPGR gene therapy. In the cases of the male (M) phenotype where the X-inactivation was skewed, the pattern was similar in both eyes, suggesting that the mechanism is not truly random but may have an underlying genetic basis.

X-linked retinitis pigmentosa is an amenable disease to be treated by gene therapy. Codon optimisation has overcome the challenge of designing an vector without mutations, and with a therapeutic effect in different animal models. With the RPGR gene therapy clinical trials still in the early stages, the confirmation of the safety, tolerability and potency of the therapy is still ongoing.