Early clinical results report gene therapy treatment for X-linked retinitis pigmentosa caused by mutations in RPGR

Research from the University of Oxford has reported early results from 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. 18 patients had 6-month follow up data focused on safety outcomes with additional secondary outcomes with preliminary results from visual acuity, microperimetry and central retinal thickness. The patients were treated with increasing doses of a viral vector carrying an RPGR gene (RP GTPase regulator (RPGR)) in which the DNA had been altered, but in a manner that still allowed correct production of the missing protein.


X-linked retinitis pigmentosa (XLRP) is an incurable genetic disease that causes blindness in males and affects approximately one in 15,000 people. The disease is caused by a defect in the RPGR gene which is located on the X-chromosome.  Mutations in the RPGR gene can be associated with a rod-cone or cone-rod dystrophy phenotype. The most common presentation is as a rod-cone dystrophy. It is one of the most severe forms of RP with nyctalopia in most affected males before 10 years of age and progression to legal blindness by the third to fourth decade. The disorder is initially identified with difficulties in scotopic visual function, where there is a predominant loss of rod photoreceptors. Simultaneously, peripheral vision deteriorates, resulting in visual field constriction on perimetry findings. The majority of cases present with a rod-cone dystrophy-type disease progression, where central visual acuity is initially less impaired than the peripheral field loss. The fovea is ultimately affected in all cases during the late stages of the disease by subsequent cone photoreceptor degeneration.


In the study, 18 patients with genetically confirmed variants in RPGR were recruited into 6 cohorts of 3 patients, each receiving increasing concentrations from 5 × 10^10 genomic particles (gp) ml−1 to 5 × 10^12 gp ml−1, using AAV8-coRPGR via a subretinal injection.  In follow up to six-month data, the researchers suggested that the vector did not have any dose-limiting toxicities, while the secondary outcomes provided visual acuity, microperimetry and central retina thickness results.  BCVA (ETRS letters) showed treated eyes (n = 18) with a baseline mean of 57.2 letters, compared to a mean of 57.1 at 6 months, i.e., a change at 6 months of −0.1 letters (95% CI −2.8 to 2.6). Untreated eyes (n = 18) had a baseline mean of 65.9 letters, compared to a mean of 66.7 letters at 6 months, i.e., at 6 months +0.8 letters (95% CI −1.3 to 2.9). Mean microperimetry had a baseline mean of 3.2 dB compared with a mean of 3.6 dB at 6 months, i.e., a + 0.4 dB change (95% CI −0.7 to 1.7). And finally, in terms of central retinal thickness assessment, there was a baseline mean of 143.6μm, compared to a mean of 132.7μm at 6 months, i.e., a mean change of −10.8μm (95% CI −25.1 to 3.5).  In essence, it will be at least 12, 24 and 36 months later before a clearer picture can adjudicate on how the technology might work.

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