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Purpose: To assess the safety and efficacy of AAV5-hRKp.RPGR in participants with retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP)., Design: Open-label, phase 1/2 dose escalation/expansion study (ClinicalTrials.gov Identifier: NCT03252847)., Methods: Males (≥5 years old) with XLRP-RPGR were evaluated. In the dose escalation phase, subretinal AAV5-hRKp.RPGR (low: 1.0 × 10 11 vg/ml; intermediate: 2.0 × 10 11 vg/ml; high: 4.0 × 10 11 vg/ml) was administered to the poorer-seeing eye (n = 10). Dose confirmation (intermediate dose) was carried out in 3 pediatric participants. In the dose expansion phase, 36 participants were randomized 1:1:1 to immediate (low or intermediate dose) or deferred (control) treatment. The primary outcome was safety. Secondary efficacy outcomes included static perimetry, microperimetry, vision-guided mobility, best corrected visual acuity, and contrast sensitivity. Safety and efficacy outcomes were assessed for 52 weeks for immediate treatment participants and 26 weeks for control participants., Results: AAV5-hRKp.RPGR was safe and well tolerated, with no reported dose-limiting events. Most adverse events (AEs) were transient and related to the surgical procedure, resolving without intervention. Two serious AEs were reported with immediate treatment (retinal detachment, uveitis). A third serious AE (increased intraocular pressure) was reported outside the reporting period. All ocular inflammation-related AEs responded to corticosteroids. Treatment with AAV5-hRKp.RPGR resulted in improvements in retinal sensitivity and functional vision compared with the deferred group at Week 26; similar trends were observed at Week 52., Conclusions: AAV5-hRKp.RPGR demonstrated an anticipated and manageable AE profile through 52 weeks. Safety and efficacy findings support investigation in a phase 3 trial., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to analyze the clinical spectrum and natural history of CDH23-associated Usher syndrome type ID (USH1D)., Methods: Molecularly-confirmed individuals had data extracted from medical records. Retinal imaging was extracted from an in-house database. The main outcome measurements were retinal imaging and electroretinography (ERG) and clinical findings, including age of onset, symptoms, best-corrected visual acuity (BCVA), outer nuclear layer (ONL) thickness, ellipsoid zone width (EZW), and hyperautofluorescent ring area., Results: Thirty-one patients were identified, harboring 40 variants in CDH23 (10 being novel). The mean (range, ±SD) age of symptom onset was 10.1 years (range = 1-18, SD = ±4.1). The most common visual symptoms at presentation were nyctalopia (93.5%) and peripheral vision difficulties (61.3%). The mean BCVA at baseline was 0.25 ± 0.22 in the right eyes and 0.35 ± 0.58 LogMAR in the left eyes. The mean annual loss rate in BCVA was 0.018 LogMAR/year over a mean follow-up of 9.5 years. Individuals harboring the c.5237G>A p.(Arg1746Gln) allele had retinitis pigmentosa (RP) sparing the superior retina. Seventy-seven percent of patients had hyperautofluorescent rings in fundus autofluorescence. Full-field and pattern ERGs indicated moderate-severe rod-cone or photoreceptor dysfunction with relative sparing of macular function in most patients tested. Optical coherence tomography (OCT) revealed intraretinal cysts in the transfoveal B-scan of 13 individuals (43.3%). The rate of EZW and ONL thickness loss was mild and suggestive of a wide window of macular preservation., Conclusions: Despite the early onset of symptoms, USH1D has a slowly progressive phenotype. There is high interocular symmetry across all parameters, making it an attractive target for novel therapies.

Purpose: To analyze the natural history of EFEMP1-associated autosomal dominant drusen (ADD)., Methods: In this retrospective observational study of molecularly confirmed patients with ADD, data and retinal imaging were extracted from an in-house database. The main outcome measurements were best-corrected visual acuity (BCVA), refraction, and retinal imaging, including quantitative analyses of the outer nuclear layer (ONL) thickness and pigmented epithelium detachment area, as well as qualitative analyses., Results: The study included 44 patients (34 females and 10 males). The mean ± SD age of symptom onset was 40.1 ± 6.59 years of age (range, 25-52). Fourteen patients were asymptomatic during their entire follow-up. The most common symptoms at presentation were reduced vision (70%) and distortion in central vision (53%). Most subjects were emmetropic. The mean BCVA (logMAR) at baseline was 0.27 ± 0.41 (range, -0.1 to 2.1) in right eyes and was 0.19 ± 0.32 (range, -0.2 to 1.3) in left eyes. After a mean follow-up of 7.9 years, BCVA was reduced to 0.59 ± 0.66 (range, -0.1 to 2.1) in right eyes and 0.5 ± 0.72 (range, -0.1 to 2.4) in left eyes, values that were significantly different than baseline (P < 0.0001 and P < 0.0014, respectively). Fifteen eyes showed active or inactive choroidal neovascularization (CNV). BCVA differed significantly (P = 0.0004) between eyes with and without CNV at a comparable mean age. The ONL had a slow rate of thinning longitudinally, which significantly correlated with BCVA., Conclusions: Despite the late onset and relatively good prognosis of ADD, CNVs are more frequent than previously reported and are associated with a worse prognosis. Further research is necessary to elucidate gender associations.

Purpose: To investigate the long-term natural history of retinal function of achromatopsia (ACHM)., Methods: Subjects with molecularly confirmed ACHM were recruited in a prospective cohort study of mesopic microperimetry. Coefficient of repeatability and intraclass correlation coefficient (ICC) of mean sensitivity (MS) were calculated. Best-corrected visual acuity (BCVA), bivariate contour ellipse area (BCEA), contrast sensitivity (CS), MS, total volume (VTOT), and central field volume (V5°) from volumetric and topographic analyses were acquired. Correlation of functional parameters with structural findings from optical coherence tomography (OCT) was performed., Results: Eighteen subjects were recruited. Mean follow-up was 7.2 years. The MS test-retest repeatability coefficient was 1.65 decibels (dB), and the ICC was 0.973 (95% confidence interval, 0.837-0.98). Mean MS was similar for right and left eyes (16.97dB and 17.14dB, respectively). A negative significant correlation between logMAR BCVA and the retinal sensitivity indices (MS, VTOT, V5°) was found. A significant negative correlation between logCS and MS, VTOT, and V5° was also observed. BCVA and BCEA improved during follow-up. Mean CS, MS, VTOT, and V5° at final follow-up were similar to baseline. MS was similar between CNGA3- and CNGB3-ACHM. Patients with and without the presence of a foveal ellipsoid zone on OCT had similar MS (16.64 dB and 17.17 dB, respectively)., Conclusions: We demonstrate a highly reproducible assessment of MS. Retinal function including MS, volumetric indices, and CS are stable in ACHM. Improvement of fixation stability and small changes of BCVA over time may be part of the natural history of the disease.

Purpose: To perform deep phenotyping of subjects with PDE6C achromatopsia and examine disease natural history., Methods: Eight subjects with disease-causing variants in PDE6C were assessed in detail, including clinical phenotype, best-corrected visual acuity, fundus autofluorescence, and optical coherence tomography. Six subjects also had confocal and nonconfocal adaptive optics scanning light ophthalmoscopy, axial length, international standard pattern and full-field electroretinography (ERG), short-wavelength flash (S-cone) ERGs, and color vision testing., Results: All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia. We identified three novel disease-causing variants and provide phenotype data associated with nine variants for the first time. No subjects had foveal hypoplasia or residual ellipsoid zone (EZ) at the foveal center; one had an absent EZ, three had a hyporeflective zone, and four had outer retinal atrophy. The mean width of the central EZ lesion on optical coherence tomography at baseline was 1923 μm. The mean annual increase in EZ lesion size was 48.3 μm. Fundus autofluorescence revealed a central hypoautofluorescence with a surrounding ring of increased signal (n = 5). The mean hypoautofluorescent area at baseline was 3.33 mm2 and increased in size by a mean of 0.13 mm2/year. Nonconfocal adaptive optics scanning light ophthalmoscopy revealed residual foveal cones in only one of two cases. Full-field ERGs were consistent with severe generalized cone system dysfunction but with relative preservation of S-cone sensitivity., Conclusions: PDE6C retinopathy is a severe cone dysfunction syndrome often presenting as typical achromatopsia but without foveal hypoplasia. Myopia and slowly progressive maculopathy are common features. There are few (if any) residual foveal cones for intervention in older adults.

Purpose: Quantitative analysis of hyperautofluorescent rings and progression in subjects with retinitis pigmentosa associated with retinitis pigmentosa GTPase regulator (RPGR) gene mutations., Methods: Prospective observational study of 46 subjects. Ring area, horizontal and vertical diameter measurements taken from outer and inner ring borders. Intraobserver repeatability, baseline measurements, progression rates, interocular symmetry, and association with age and genotype were investigated., Results: Baseline ring area was 11.8 ± 13.4 mm and 11.4 ± 13.2 mm for right and left eyes, respectively, with very strong interocular correlation (r = 0.9398; P < 0.0001). Ring area constriction was 1.5 ± 2.0 mm/year and 1.3 ± 1.9 mm/year for right and left eyes, respectively, with very strong interocular correlation (r = 0.878, P < 0.0001). Baseline ring area and constriction rate correlated negatively with age (r = -0.767; P < 0.0001 and r = -0.644, P < 0.0001, respectively). Constriction rate correlated strongly with baseline area (r = 0.850, P < 0.0001). Age, but not genotype, exerted a significant effect on constriction rates (P < 0.0001), with greatest rates of progression seen in younger subjects. An exponential decline overall was found., Conclusion: This study provides disease-specific baseline values and progression rates together with a repeatability assessment of fundus autofluorescence metrics. Our findings can guide future treatment trials and contribute to the clinical care of patients with RPGR-associated retinitis pigmentosa.

Purpose: To characterize bilateral visual function, interocular variability and progression by using static perimetry-derived volumetric and pointwise metrics in subjects with retinitis pigmentosa associated with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene., Methods: This was a prospective longitudinal observational study of 47 genetically confirmed subjects. Visual function was assessed with ETDRS and Pelli-Robson charts; and Octopus 900 static perimetry using a customized, radially oriented 185-point grid. Three-dimensional hill-of-vision topographic models were produced and interrogated with the Visual Field Modeling and Analysis software to obtain three volumetric metrics: VTotal, V30, and V5. These were analyzed together with Octopus mean sensitivity values. Interocular differences were assessed with the Bland-Altman method. Metric-specific exponential decline rates were calculated., Results: Baseline symmetry was demonstrated by relative interocular difference values of 1% for VTotal and 8% with V30. Degree of symmetry varied between subjects and was quantified with the subject percentage interocular difference (SPID). SPID was 16% for VTotal and 17% for V30. Interocular symmetry in progression was greatest when quantified by VTotal and V30, with 73% and 64% of subjects possessing interocular rate differences smaller in magnitude than respective annual progression rates. Functional decline was evident with increasing age. An overall annual exponential decline of 6% was evident with both VTotal and V30., Conclusions: In general, good interocular symmetry exists; however, there was both variation between subjects and with the use of various metrics. Our findings will guide patient selection and design of RPGR treatment trials, and provide clinicians with specific prognostic information to offer patients affected by this condition.

PurposeMutations in six genes have been associated with achromatopsia (ACHM): CNGA3, CNGB3, PDE6H, PDE6C, GNAT2, and ATF6. ATF6 is the most recent gene to be identified, though thorough phenotyping of this genetic subtype is lacking. Here, we sought to test the hypothesis that ATF6-associated ACHM is a structurally distinct form of congenital ACHM.MethodsSeven genetically confirmed subjects from five nonconsanguineous families were recruited. Foveal hypoplasia and the integrity of the ellipsoid zone (EZ) band (a.k.a., IS/OS) were graded from optical coherence tomography (OCT) images. Images of the photoreceptor mosaic were acquired using confocal and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). Parafoveal cone and rod density values were calculated and compared to published normative data as well as data from two subjects harboring CNGA3 or CNGB3 mutations who were recruited for comparative purposes. Additionally, nonconfocal dark-field AOSLO images of the retinal pigment epithelium were obtained, with quantitative analysis performed in one subject with ATF6-ACHM.ResultsFoveal hypoplasia was observed in all subjects with ATF6 mutations. Absence of the EZ band within the foveal region (grade 3) or appearance of a hyporeflective zone (grade 4) was seen in all subjects with ATF6 using OCT. There was no evidence of remnant foveal cone structure using confocal AOSLO, although sporadic cone-like structures were seen in nonconfocal split-detection AOSLO. There was a lack of cone structure in the parafovea, in direct contrast to previous reports.ConclusionsOur data demonstrate a near absence of cone structure in subjects harboring ATF6 mutations. This implicates ATF6 as having a major role in cone development and suggests that at least a subset of subjects with ATF6-ACHM have markedly fewer cellular targets for cone-directed gene therapies than do subjects with CNGA3- or CNGB3-ACHM.

PurposeTo describe the earliest features of ABCA4-associated retinopathy.DesignCase series.ParticipantsChildren with a clinical and molecular diagnosis of ABCA4-associated retinopathy without evidence of macular atrophy.MethodsThe retinal phenotype was characterized by color fundus photography, OCT, fundus autofluorescence (FAF) imaging, electroretinography, and in 2 patients, adaptive optics scanning laser ophthalmoscopy (AOSLO). Sequencing of the ABCA4 gene was performed in all patients.Main outcome measuresVisual acuity, OCT, FAF, electroretinography, and AOSLO results.ResultsEight children with ABCA4-associated retinopathy without macular atrophy were identified. Biallelic variants in ABCA4 were identified in all patients. Four children were asymptomatic, and 4 reported loss of VA. Patients were young (median age, 8.5 years; interquartile range, 6.8 years) with good visual acuity (median, 0.155 logarithm of the minimum angle of resolution [logMAR]; interquartile range, 0.29 logMAR). At presentation, the macula appeared normal (n = 3), had a subtly altered foveal reflex (n = 4), or demonstrated manifest fine yellow dots (n = 1). Fundus autofluorescence identified hyperautofluorescent dots in the central macula in 3 patients, 2 of whom showed a normal fundus appearance. Only 1 child had widespread hyperautofluorescent retinal flecks at presentation. OCT imaging identified hyperreflectivity at the base of the outer nuclear layer in all 8 patients. Where loss of outer nuclear volume was evident, this appeared to occur preferentially at a perifoveal locus. Longitudinal split-detector AOSLO imaging in 2 individuals confirmed that the greatest change in cone spacing occurred in the perifoveal, and not foveolar, photoreceptors. Electroretinography showed a reduced B-wave-to-A-wave ratio in 3 of 5 patients tested; in 2 children, recordings clearly showed electronegative results.ConclusionsIn childhood-onset ABCA4-associated retinopathy, the earliest stages of macular atrophy involve the parafovea and spare the foveola. In some cases, these changes are predated by tiny, foveal, yellow, hyperautofluorescent dots. Hyperreflectivity at the base of the outer nuclear layer, previously described as thickening of the external limiting membrane, is likely to represent a structural change at the level of the foveal cone nuclei. Electroretinography suggests that the initial site of retinal dysfunction may occur after phototransduction.