Fragile Maculas in Patients with Retinal Degeneration due to RPGR-ORF15 Mutations: Spatio-temporal Models of Disease Progression

Abstract

Purpose : One of the most common molecular forms of retinitis pigmentosa (RP) is an X-linked (XL) disease caused by RPGR mutations in the ORF15 exon. Promising treatments include gene augmentation therapy demonstrating arrest of photoreceptor degeneration (Beltran et al. PNAS, 2012&2015). We measured macular photoreceptor structure and RPE disease in patients to evaluate retinal targets for eventual gene therapy trials.

Methods : We characterized RPGR-ORF15 patients (n=39, ages 10-51) with SD-OCT, autofluorescence, BCVA and foveal sensitivities.

Results : Refractions tended to be myopic (range -14D to +3D, median=-4D). 76% of patients had a BCVA of 20/32 or lower (range 20/20 to LP). Across the macula, there was a spectrum of disease severity and abnormalities were distributed across a range of spatial patterns. All eyes had abnormal macular structure by OCT. In 32 eyes, a detectable EZ layer extended only to 1.1° on average from the fovea along the horizontal and vertical meridians. Many eyes demonstrated a partial or complete parafoveal degeneration. In the perifovea, the majority of eyes showed no detectable EZ layer. In a few cases, EZ layer could be measured perifoveally, with a tendency of superior over inferior structural retention, which was also apparent on autofluorescence imaging. Foveal structure was an excellent predictor of foveal function. Macular imaging results were consistent with the hypothesis that RPGR-ORF15 disease showed a progressive spatio-temporal time course that could be described by the sum of central and peripheral components, each with a different natural history. Central disease would start parafoveally, encircle the fovea and annular fronts would expand centrifugally and centripetally. Peripheral disease would either start as a midperipheral annulus and expand centripetally towards the macula, or start in the inferior retina with a disease front sweeping across the macula from inferior to superior retina.

Conclusions : In most ORF15 patients, the EZ layer is either nondetectable or limited to the foveal region. Structural and functional measures suggest fragile maculas are not targets of experimental subretinal therapies. Future studies will evaluate extramacular regions in search of retained rods and cones that could be targeted with subretinal gene therapy.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.