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Purpose Choroideremia (CHM) is a X-chromosomal disorder leading to blindness by progressive degeneration of choroid, retinal pigment epithelium (RPE), and retinal neurons. A current clinical gene therapy trial (NCT01461213) showed promising safety and efficacy data in a carefully selected patient population. The present study was performed to shed light on pre-treatment characteristics of a larger cohort of CHM patients using a high resolution multi-modal approach. Methods In a retrospective cross-sectional study, data from 58 eyes of 29 patients with clinically confirmed CHM were analysed including best-corrected visual acuity (BCVA), refractive error, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), perimetry, and tonometry. Residual retinal volume, area of residual RPE, and foveal thickness were quantified to further define natural disease progression and assess symmetry. Results We evaluated 98 data points of BCVA [0.34 ± 0.06 (logMAR); mean ± 95 % confidence interval], 80 of IOP (14.6 ± 0.6 mmHg), and 98 of refraction (−2.16 ± 1.08 spherical equivalent). Visual fields ( n   = 76) demonstrated variable degrees of concentric constriction (54 % <10°, 25 % 10–30°, 21 % >30°). Mean residual RPE area on FAF ( n   = 64) measured 8.47 ± 1.91 mm 2 (range 0.30–38.5 mm 2 ), while mean neuroretinal volume ( n   = 42) was found to be 1.76 ± 0.12 mm 3 . Age at examination was exponentially associated with BCVA, while logarithmic functions best described progressive loss of retinal area and volume. A high degree of left to right symmetry was found in all modalities with structural markers showing the best correlation ( r 2 area  = 0.83; r 2 volume  = 0.75). Conclusion Analysis of these widely available clinical data defines the natural disease characteristics of a relevant patient population eligible for gene therapeutic intervention. In the wake of preliminary reports on safety and efficacy of CHM gene therapy (NCT01461213), this multi-modal assessment of a cohort of CHM patients provides important evidence of the natural rate of disease progression and degree of symmetry between eyes.

X-linked retinoschisis (XLRS) is a potential target for gene supplementation approaches. To establish potential structural and functional endpoints for clinical trials, a comprehensive understanding of the inter-eye symmetry, relationship between structural and functional parameters, and disease progression is vital. In this retrospective multicentre study, 118 eyes of 59 XLRS patients with mutations were assessed. Information from center databases included: variant; age at presentation; best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume (MV) at presentation and at the last follow up; full-field electroretinogram (ERG) findings; presence of peripheral retinoschisis and complications (vitreous hemorrhage, retinal detachment); treatment with systemic or topical carbonic anhydrase inhibitors (CAI). Inter-eye symmetry revealed strong correlation in CRT ( = 0.77; < 0.0001) and moderate correlations in MV ( = 0.51, < 0.0001) and BCVA ( = 0.49; < 0.0001). Weak or no correlations were observed between BCVA and structural parameters (CRT, MV). Peripheral retinoschisis was observed in 40 (68%), retinal detachment in 9 (15%), and vitreous hemorrhage in 5 (8%) patients, respectively. Longitudinal examinations (mean, 4.3 years) showed no BCVA changes; however, a reduction of the CRT ( = 0.02), and MV ( = 0.01) was observed. Oral and/or topical CAI treatment did not significantly alter the CRT ( = 0.34). The XLRS phenotype demonstrates a strong CRT symmetry between the eyes within individual patients and stable BCVA over several years. BCVA exhibits a weak correlation with the morphological parameters of retinal thickness (CRT MV). In our cohort, longitudinal functional changes were not significant, likely attributed to the short average follow-up period. Furthermore, CAI treatment didn't influence both morphological and functional outcomes.

Objectives To analyse the incidence of persistence and recurrence after the peeling of idiopathic epiretinal membrane (ERM) and to describe its clinical features. Methods This retrospective study included 666 eyes (645 patients) that underwent macular surgery for ERM removal. Optical coherence tomographic (OCT) images taken within three months after surgery and at the following visits, clinical parameters and surgery related factors were analysed to investigate the incidence and associated factors of ERM persistence and recurrence. Postoperative ERM types were categorised depending on the size ( < 100 µm, ≥100 µm) and the location (foveal, parafoveal, outside the parafovea) Results The mean follow-up time was 29.4 months. ERM persistence (examination within 3 months) was found in 29.6% of all eyes. Only 1.9% of the eyes presented foveal ERM persistence. Foveal recurrence, defined as reappearance or growth of persistent ERM covering the fovea, was found in 8.2%. In 84.4% of eyes with foveal ERM recurrence, postoperative persistence of ERM of varying severity were identified. None of the pre-operative or surgery related factors were found significantly associated with ERM recurrence. Persistent ERM within the parafovea was the most significant risk factor for foveal ERM recurrence. Conclusion Recurrence of ERM is generally preceded by the persistence of ERM fragments found in the early postoperative period. Growth of ERM persistence from the parafoveal region was often the origin of foveal ERM recurrence. Insufficient peeling seems to be the most significant predisposing factor for foveal ERM recurrence.

Ocular gene therapy has evolved rapidly into the clinical realm due to promising pre-clinical proof-of-concept studies, recognition of the high unmet medical need of blinding disorders, and the excellent safety profile of the most commonly used vector system, the adeno-associated virus (AAV). With several trials exposing subjects to AAV, investigators independently report about cases with clinically evident inflammation in treated eyes despite the concept of ocular immune privilege. Here, we provide a detailed analysis of innate and adaptive immune response to clinical-grade AAV8 in non-human primates and compare this to preliminary clinical data from a retinal gene therapy trial for CNGA3-based achromatopsia (ClinicalTrials.gov: 02610582). Reichel et al. (2017) provide analysis of immune response to clinical-grade AAV8 in primates, along with preliminary clinical data from a gene therapy trial. The high-dose group of animals demonstrated mononuclear infiltrates, upregulation of IFNγ-mediated cytokines, and activation of adaptive immune response cells four weeks after injection.

The purpose of this study was to compare the retention rate of Adeno-associated viral vector (AAV) gene therapy agents within different subretinal injection systems. The retention of AAV serotype 2-based voretigene neparvovec (VN) and a clinical-grade AAV serotype 8 vector within four different subretinal cannulas from two different manufacturers was quantified. A standardized qPCR using the universal inverted terminal repeats as a target sequence was developed. The instruments compared were the PolyTip® cannula 25 g/38 g by MedOne Surgical, Inc., Sarasota, FL, USA, and three different subretinal injection needles by DORC, Zuidland, The Netherlands (1270.EXT Extendible 41G subretinal injection needle (23G), DORC 1270.06 23G Dual bore injection cannula, DORC 27G Subretinal injection cannula). The retention rate of VN and within the DORC products (10–28%) was comparable to the retention rate (32%) found for the PolyTip® cannula that is mentioned in the FDA-approved prescribing information for VN. For the AAV8 vector, the PolyTip® cannula showed a retention rate of 14%, and a similar retention rate of 3–16% was found for the DORC products (test–retest variability: mean 4.5%, range 2.5–20.2%). As all the instruments tested showed comparable retention rates, they seem to be equally compatible with AAV2- and AAV8-based gene therapy agents.

PurposeThe purpose of this study was to characterise alterations in colour discrimination in a cohort of patients with choroideremia prior to gene therapy, using a test previously validated for use in patients with retinal dystrophies.MethodsWe tested 20 eyes of 10 patients with a diagnosis of choroideremia and an age-matched cohort of 10 eyes of 10 normal controls using the “Cambridge Colour Test” (CCT), in which subjects are required to distinguish the gap in a C presented in one of 4 orientations in a Stilling-type array. Colour discrimination was probed along eight axes in the CIE L*u*v* colour space, and the resulting data were plotted in the CIE 1976 chromaticity diagram and fitted with least-squares ellipses. Subsequently, we estimated the achromatic area for each subject by calculating the area of the resultant discrimination ellipse and calculated sensitivity thresholds along relevant colour confusion axes.ResultsColour discrimination—as quantified by log10 of the ellipse area expressed in square 1/1000th2 units in CIE 1976—was 2.26 (range 1.82 to 2.67) for normal subjects and 3.85 (range 2.35 to 5.41) for choroideremia patients. There was a statistically significant correlation between both achromatic area and red-green colour discrimination at the CCT and BCVA, and to a lesser degree between blue colour discrimination at the CCT and BCVA. The majority of ellipses in choroideremia were aligned close to the tritan axis, and loss of sensitivity was significantly larger in the tritan direction than in the red-green.ConclusionsThe majority of our patients demonstrated greater loss in tritan discrimination than in red-green colour discrimination using the CCT. There was a significant correlation between achromatic area and BCVA. In keeping with our current understanding of the machinery of colour vision, there was a significant correlation between BCVA and colour discrimination thresholds, which was stronger for red-green colour discrimination, than for tritan colour discrimination. We propose that this and similar tests of colour discrimination may prove to be suitable tools for assessing functional outcomes in gene therapy trials for choroideremia.

AimsTo determine long-term safety and efficacy outcomes of a subretinal gene therapy for CNGA3-associated achromatopsia. We present data from an open-label, nonrandomised controlled trial (NCT02610582).MethodsDetails of the study design have been previously described. Briefly, nine patients were treated in three escalating dose groups with subretinal AAV8.CNGA3 gene therapy between November 2015 and October 2016. After the first year, patients were seen on a yearly basis. Safety assessment constituted the primary endpoint. On a secondary level, multiple functional tests were carried out to determine efficacy of the therapy.ResultsNo adverse or serious adverse events deemed related to the study drug occurred after year 1. Safety of the therapy, as the primary endpoint of this trial, can, therefore, be confirmed. The functional benefits that were noted in the treated eye at year 1 were persistent throughout the following visits at years 2 and 3. While functional improvement in the treated eye reached statistical significance for some secondary endpoints, for most endpoints, this was not the case when the treated eye was compared with the untreated fellow eye.ConclusionThe results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor.