Figure 5.

I. Retinal disease phenotypes caused by RPGR-ORF15 mutations in human patients and in dogs. (A) Different patterns of photoreceptor topography in two XLRP patients with RPGR mutations. ONL thickness topography is mapped to a pseudocolor scale. (Inset) Representative normal subject. Locations of fovea and optic nerve (ON) are shown. (B) Different patterns of photoreceptor topography in the canine models of RPGR-ORF15; mapping as performed with the human data. (Inset) Map of a representative wild-type dog with location of ON labeled. (C) ONL thickness profile along the vertical meridian (Inset) comparing XLPRA1 and XLPRA2 of different ages (thin traces) versus normal results (gray band). Mean (±SD) results are from groups of younger (7–28 weeks) and older (36–76 weeks) dogs. The thicker red line represents the data from the oldest dogs examined (>144 weeks old). Brackets mark the location of the high photoreceptor density corresponding to the canine visual streak. Figures and legends in I modified from Beltran WA, Cideciyan AV, Lewin AS, et al. Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proc Natl Acad Sci U S A. 2012;109:2132–2137. © 2012 The Authors. II, III. Efficacy and long-term stability of gene therapy intervention at (II) mid-stage and (III) late-stage disease. (A) Pseudocolor maps of ONL thickness topography in XLPRA2 dogs treated at 12 (mid-stage) and 26 (late-stage) weeks of age. Dashed outline is the retinal region corresponding to the subretinal vector bleb at treatment. Schematic, right, paired loci across the treatment boundary and in the inferior retina chosen for quantitative evaluation. Eyes are shown as equivalent right eyes with optic nerve and major blood vessels overlaid for ease of comparability. T, temporal; N, nasal retina. (B) Progressive changes in ONL fraction recorded serially between 11 (mid-stage) and 25 (late-stage) weeks through to 130 weeks of age in treated (green) and untreated (red) loci in the superior and inferior retinas of three XLPRA2 dogs treated for each disease stage. None of the three late-stage treated eyes received injection in the inferior retina; thus, only untreated loci are shown in inferior retina. Vertical green arrows depict the timing of treatment. Dashed lines show the range of ONL fraction expected in wild-type eyes or natural history of progression in untreated XLPRA2 eyes. Smaller symbols represent the individual data and larger symbols with error bars represent mean ± SD; *P < 0.01 for paired t-tests between treated and untreated loci. (C) Retinal morphology at 113 weeks of age in the untreated (UnTx) and treated (Tx) areas of a dog injected at mid- and late-stage disease and immunohistochemistry labeling of stable human RPGR transgene product, which is present only in treated areas. IV. Long-term durability of retinal function after gene therapy intervention at late-stage disease. Representative ERG traces of rod and mixed rod–cone responses recorded dark-adapted and cone responses to single stimuli, or 29-Hz cone flicker recorded light-adapted. Figures and legends in II, III, and IV modified from Beltran WA, Cideciyan AV, Iwabe S, et al. Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease. Proc Natl Acad Sci U S A. 2015;112:E5844–E5853. © 2015 The Authors.