A natural history of XLRP from RP2 mutations aim to facilitate trial endpoints for future clinical studies.

Researchers at the UCL Institute of Ophthalmology, London and Moorfields Eye Hospital NHS Foundation Trust has reported a novel history of RP2 mutations arising from X-linked retinitis pigmentosa (XLRP).  XLRP is one of the most severe forms of retinitis pigmentosa (RP), 80% of which arises from two genes – RPGR (retinitis pigmentosa GTPase regulator) and RP2 (retinitis pigmentosa 2).  While there are significant natural history data on RPGR, the research team in the UK suggested that limited data on RP2 natural history shows only small samples and / or cross-sectional designs.  Given the considerable gene therapy studies on-going for retinal clinical research, the current UK study aimed to characterize the key outcomes to be measured for future clinical trials.

Mutations in RP2 account for 10–20% of XLRP cases and the encoded RP2 protein is implicated in ciliary trafficking of myristoylated and prenylated proteins in photoreceptor cells. To date >70 mutations in RP2 have been identified and how these mutations disrupt the function of RP2 is not fully understood. RP2 patients present a severe phenotype with early macular involvement and vision loss from adolescence and early adulthood. The current natural history studies were required to identify potential outcome metrics for clinical trials and provide prognostic indicators for patients. In this study, 24 mutations were identified in RP2, 13 of which were novel, with a high prevalence of missense variant c.352C>T p.(Arg118Cys) and nonsense variant c.358C>T p.(Arg120*), affecting two and five unrelated families, respectively.

Following the recruitment and analysis, a total of 47 affected males (median baseline age: 20 years, IQR: 12.5-36.5) were included, and 41 had two or more visits (median follow-up: 8.0 years, IQR: 3.2-14.5). A total of 24 RP2 variants were identified, 13 of which were novel. BCVA dropped from 0.66 LogMAR at baseline (IQR, 0.35-1.4) to 1.3 LogMAR at the most recent visit (IQR: 0.6-1.4). SD-OCT revealed a prevalent outer retinal atrophy (n = 23/35, 65.7%), and measurable ellipsoid zone (EZ) width at baseline in 34.3% of patients (n = 12). Age significantly affected all quantitative measures (p < 0.001) except EZ width (p = 0.58), with exponential decays of 46-49% and 12.6-33.9% per decade for BCVA and SD-OCT measures, respectively. RP2 patients exhibited rapid progression to outer retina atrophy and early macular involvement with substantial vision loss by age 30-40.  In addition, the majority of eyes assessed in EZ measures (66%) showed severe disruption of the EZ and atrophy of the outer retina and for central retinal thickness (CRT), patients had a median at baseline of 118 µm (IQR: 94 to 145) which dropped to a median of 96 µm (IQR: 83 to 129.5) at the last visit. For a measurement of photoreceptors and retinal pigment epithelium (PR+RPE), XLRP patients showed a median PR+RPE thickness of 41.5 µm (IQR: 25 to 70.25) at baseline, which reduced to 25 µm (IQR: 18 to 38) at the last visit. In summary, the longitudinal analysis revealed significant age-related loss of BCVA (46–49% loss per 10 years), CRT (13–14% loss per 10 years) and PR+RPE (27–34% loss per 10 years). In conclusion of the research study, researchers commented that “we found a severe disease phenotype, with early macular involvement, atrophy of the outer retina and substantial central vision loss by the third–fourth decades of life. All clinical measures assessed showed a substantial rate of loss, with EZ width being largely not measurable from 25 years of age. BCVA and outer retina thickness at the fovea seemed to offer monitoring capability for some 10 more years”. Finally, PR+RPE thickness could be a valuable quantitative and objective surrogate of central visual function and microperimetry may provide high reproducibility to detect disease progression in other forms of RP in younger cohorts, including RPGR-associated RP.