Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.

Objective The effectiveness of annual diabetic eye exams in children is unclear. We sought to determine the prevalence and onset of ocular pathology in children with diabetes mellitus (DM), identify risk factors for ocular disease, and recommend a screening regimen for asymptomatic children. Design Retrospective consecutive cohort study. Subjects Children less than age 18 years with type 1 or 2 DM examined over a 4 year period. Methods All children underwent a complete eye exam, including dilated fundoscopy and cycloplegic refraction. A literature review was performed, identifying the youngest reported age and shortest reported duration of DM prior to the diagnosis of diabetic retinopathy. Main outcome measures Prevalence of diabetic retinopathy, cataract, high refractive error, and strabismus. Results 370 children (mean age 11.2 years, range 1–17.5) had 693 examinations, with mean DM duration 5.2 years (range 0.1–16.2), mean HbA1c 8.6 (range 5 to ≥14). No children had diabetic retinopathy. 12 had cataract; 5 required extraction but were identified by decreased vision, not diabetic screening. 19 had strabismus; only one was microvascular paralytic strabismus. 41 had high refractive error. There were no associations between these conditions and duration or control of DM. In the literature, the youngest age at diagnosis of severe diabetic retinopathy was 15 years and the shortest duration of disease was 5 years. Conclusion Diabetic retinopathy is rare in children regardless of duration and control of DM. Based upon our study and literature review, screening examinations for type 1 diabetics could begin at age 15 years or at 5 years after the diagnosis of DM, whichever occurs later, unless the child is judged by the endocrinologist as being at unusally high risk. Other ocular complications are identifiable through existing amblyopia screening methods.

Objective To compare baseline characteristics, visual acuity (VA) and morphological outcomes between eyes with retinal angiomatous proliferation (RAP) and all other eyes among patients with neovascular age-related macular degeneration (NVAMD) treated with anti-vascular endothelial growth factor (anti-VEGF) drugs. Design Prospective cohort study within the Comparison of AMD Treatments Trials (CATT). Participants Patients with NVAMD Methods Reading Center staff evaluated baseline and follow-up digital color fundus photographs (CFP), fluorescein angiograms (FA), and optical coherence tomograms (OCT) of eyes having NVAMD treated with either ranibizumab or bevacizumab over a 2-year period. RAP was identified by the intense intra-retinal leakage of fluorescein in combination with other associated features. Main outcome measures VA, fluorescein leakage, scar, geographic atrophy (GA) on FA and retinal thickness, fluid and subretinal hyperreflective material (SHRM) on OCT, and number of intravitreal anti-VEGF injections at 1 and 2 years. Results RAP was present in 126 of 1183 (10.7%) study eyes at baseline. Mean VA improvement from baseline was greater (10.6 vs 6.9 letters; p=0.01) at one year but similar at 2 years (7.8 vs 6.2; p=0.34). At 1 year, eyes with RAP were more likely to have: no fluid (46 vs 26%; p<0.001) on OCT, no leakage on FA (61 vs 50%; p=0.03), and greater reduction in foveal thickness (-240 vs -161u, p<0.001). They were more likely to develop GA (24 vs 15%; p=0.01), and less likely to develop scar (17 vs 36%; p<0.001), or SHRM (36 vs 48%; p=0.01). These results were similar at 2 years. The mean change in lesion size at 1 year differed (-0.27 vs 0.27 DA; p=0.02) but was similar at 2 years (0.49 vs 0.79; p=0.26). Among eyes treated PRN, eyes with RAP received a lower mean number of injections in year 1 (6.1 vs 7.4; p=0.003) and year 2 (5.4 vs 6.6; p=0.025). Conclusions At both 1 and 2 years after initiation of anti-VEGF treatment in CATT, eyes with RAP were less likely to have fluid, FA leakage, scar, and SHRM and more likely to have GA than eyes without RAP. Mean improvement in VA was similar at 2 years.