Date of download: 6/1/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years Arch Ophthalmol. 2012;130(1):9-24. doi: /archophthalmol Figure 1. Fundus images with near-infrared illumination and sites of retinal detachments from subretinal injections of the vector gene in the 15 patients (P1-P15) with RPE65 -related Leber congenital amaurosis. The dotted circles on the images of individual patients represent the estimated areas of retinal detachment from drawings at the time of surgery. The tip of each white “syringe” indicates the retinotomy site that produced the detachment. All images are depicted as left eyes for comparability. F indicates fovea. Figure Legend:

Date of download: 6/1/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years Arch Ophthalmol. 2012;130(1):9-24. doi: /archophthalmol Figure 2. Visual function in all clinical trial patients (P1-P15) analyzed using full-field stimulus testing (FST) and the transient pupillary light reflex (TPLR). A, The mean (SD) FST sensitivity to blue stimuli was measured under dark-adapted conditions in each eye of each subject at 4 baseline visits (light gray bars) and all postoperative visits to date (dark gray bars). The normal range for FST is shown along the horizontal axis. B, Changes in FST sensitivity from mean baseline value in control and study eyes are shown. The light gray bars depict the intervisit variability at 4 baseline visits. The dark gray bars represent all available postoperative time points to date, ordered in groups for each patient. The P values refer to 2-sided paired t test statistics between indicated groups. C, The TPLR sensitivity to green flashes under dark-adapted conditions in each eye of each subject was measured at 1, 3, or 6 months after surgery (dark gray bars) compared with baseline (light gray bars). The normal range for the TPLR is shown along the horizontal axis. D, Postoperative changes in TPLR sensitivity from baseline in control and study eyes are shown. The P values refers to 2-sided paired t test statistics performed between postoperative and baseline time points. Figure Legend:

Date of download: 6/1/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years Arch Ophthalmol. 2012;130(1):9-24. doi: /archophthalmol Figure 3. Dark-adapted visual field maps of study eyes, used to localize regions of improved sensitivity after treatment. All maps are depicted as left eyes for comparability and with an overlaid schematic of retinal features (optic nerve and posterior pole vessels) for reference to fundus images (Figure 1). Loci in the visual field that consistently showed 8 dB or higher of sensitivity change during the postoperative period are highlighted (green). Estimated boundaries of blebs resulting from subretinal injections are depicted (dotted circles) on the visual field maps to determine whether there is any correspondence between the locations of injection and the responding loci. I indicates inferior visual field; N, nasal field; P, patient; S, superior field; T, temporal field. Figure Legend:

Date of download: 6/1/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years Arch Ophthalmol. 2012;130(1):9-24. doi: /archophthalmol Figure 4. Mobility performance of clinical trial patients (P1-P15) as measured by the number of navigation incidents experienced while traveling an indoor course of fixed length, for 5 ambient illumination levels. A, Changes from baseline performance for the study and control eyes of patients in cohorts 4 and 5, as a function of ambient illumination, are shown. At lower ambient illuminations, mobility was better with the study eye after treatment; at the highest illumination, patients were able to navigate almost without errors with either eye before and after treatment. There were changes in interocular differences (IODs) with treatment, with most cases showing a difference in performance of the study eyes relative to the control eyes. Values are averages of 4 repetitions performed for each illumination level except for 100 lux, at which 2 runs were performed. B, Postoperative performance differences between eyes (study eye − control eye) for each patient are shown. Most patients tended to show better relative mobility when using the study eye for lower illumination levels; there was no such effect at 100 lux. C, Differences in performance were grouped by illumination. As a group, patients show less incidents when navigating with the study eye after surgery. The black circle at the top of each panel indicates the group mean IOD (study eye − control eye); the error bars are the 95% confidence intervals. The P values (determined by use of the t test) indicate the significance of the departure of the IOD from 0 for each ambient illumination level. Figure Legend:

Date of download: 6/1/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years Arch Ophthalmol. 2012;130(1):9-24. doi: /archophthalmol Figure 5. Retinal location and instability of fixation in eyes with RPE65 -related Leber congenital amaurosis at baseline and after surgery, and their relation to changes in visual acuity (VA). Fixation clouds of all study eyes during a 10-second epoch were recorded while the patients (P1-P15) were gazing at a 1°-diameter stationary target adjusted to be visible to each eye. Both foveally fixating (A) and extrafoveally fixating (D) eyes are shown. Circular patterns show the standard grid centered on the anatomical fovea extending to radii of 1.65°, 5°, and 10°. All panels are shown in equivalent left retina representation. B, Fixation instability values are shown as change from mean baseline values at all postoperative visits in control and study eyes with foveal fixation. VAs are shown as change from mean baseline at all postoperative visits in control and study eyes with foveal (C) or extrafoveal (E) fixation. The limits for 0.30-logMAR (15 letters or 3 lines) gain or loss are shown with vertical dashed lines. N indicates nasal retina; T, temporal retina. Figure Legend:

Date of download: 6/1/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years Arch Ophthalmol. 2012;130(1):9-24. doi: /archophthalmol Figure 6. Foveal structure and quantitation of thickness using optical coherence tomography (OCT) scans in control and study eyes. A, Foveal thickness measurements in control and study eyes at baseline, and at short-term and long-term postoperative time points, are shown. Changes from baseline are displayed adjacent to the foveal thickness measurements. B, OCT scans along the horizontal meridian are shown for 4 representative patients: 1 without foveal detachment (patient 7 [P7]) and 3 with foveas detached at the time of the procedure (P1, P13, and P6). The ellipses denote the central retinal region of interest that shows changes in the inner segment/outer segment (IS/OS) lamination in 3 of the 4 study eyes at early time points but with some resolution at later times. C, Longitudinal reflectivity profiles (LRPs) through the fovea in the patients compared with a normal LRP (N). The LRPs are color coded and labeled for the outer nuclear layer (ONL), the entire region encompassing inner and outer segments (IS + OS), and the retinal pigment epithelium (RPE) to illustrate the postoperative changes. The ONL and IS + OS measurements are shown to the right of the LRPs. F, indicates fovea; FD, foveal detachment as part of the subretinal injection procedure. Figure Legend: