Optimizing Subretinal Bleb Formation for Visual Streak Involvement in a Porcine Model for Retinal Gene Therapy.

Purpose: Subretinal (SR) injection in porcine models is a promising avenue for preclinical evaluation of cell and gene therapies. Targeting of the subretinal fluid compartment (bleb) is critical to the procedure, especially if treatment of the cone-rich area centralis is required (i.e.

Dose-Dependent Progression of Chorioretinal Atrophy at the Injection Site After Subretinal Injection of rAAV2/8 in Nonhuman Primates.

Objective: Progressive retinal atrophy has been described after subretinal gene therapy utilizing the adeno-associated virus (AAV) vector platform. To elucidate whether this atrophy is a consequence of inherent properties of AAV, or if it is related to the surgical trauma of subretinal delivery, we analyzed data from an Investigational New Drug-enabling study for PDE6A gene therapy in nonhuman primates.

Design: Animal study (nonhuman primates), retrospective data analysis.

Influencing Factors on Pupillary Light Responses as a Biomarker for Local Retinal Function in a Large Normative Cohort.

Purpose: Investigating influencing factors on the pupillary light response (PLR) as a biomarker for local retinal function by providing epidemiological data of a large normative collective and to establish a normative database for the evaluation of chromatic pupil campimetry (CPC).

Methods: Demographic and ophthalmologic characteristics were captured and PLR parameters of 150 healthy participants (94 women) aged 18 to 79 years (median = 46 years) were measured with L-cone- and rod-favoring CPC protocols. Linear-mixed effects models were performed to determine factors influencing the PLR and optical coherence tomography (OCT) data were correlated with the pupillary function volume.

Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial.

Rationale: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question.

Aims: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.

The STArgardt Remofuscin Treatment Trial (STARTT): design and baseline characteristics of enrolled Stargardt patients.

This report describes the study design and baseline characteristics of patients with Stargardt disease (STGD1) enrolled in the STArgardt Remofuscin Treatment Trial (STARTT). In total, 87 patients with genetically confirmed STGD1 were randomized in a double-masked, placebo-controlled proof of concept trial to evaluate the safety and efficacy of 20 milligram oral remofuscin for 24 months. The primary outcome measure is change in mean quantitative autofluorescence value of an 8-segment ring centred on the fovea (qAF ).

Rod and Cone Function Measured Objectively by Chromatic Pupil Campimetry Show a Different Preservation Between Distinct Genotypes in Retinitis Pigmentosa.

Purpose: Verifying whether specific genotypes causing retinitis pigmentosa (RP) show differences in the preservation of rod and cone function measured by chromatic pupil campimetry (CPC).

Methods: Sixty-three RP eyes (37 male, 14-58 years) were measured using CPC with specific photopic and scotopic protocols, and the relative maximal constriction amplitudes and latencies to constriction onset were analyzed per genotype (RP due to variants in EYS, n = 14; PDE6A, n = 10; RPE65, n = 15; USH2A, n = 10; and RPGR, n = 14). Correlation analyses between the pupillary responses were performed with age, full-field stimulus threshold (FST), and optical coherence tomography (OCT) for cones and rods, respectively, to the genotype.

Central retina plays a decisive role in the suppression of pupillary escape.

Purpose: To explore the pupil redilation during persistent light exposure (pupillary escape phenomenon) at the macula and periphery with monochromatic light stimuli.

Methods: Forty healthy subjects aged 18-64 years (24 females) were examined by chromatic pupil campimetry (CPC) using red and blue 4-s stimuli of 10° radius at the center and 20°-peripheral locations one per quadrant. One glaucoma patient and one achromatopsia patient served as disease models.

Cell-specific electrical stimulation of human retinal neurons assessed by pupillary response dynamics in vivo.

Studies on the electrical excitability of retinal neurons show that photoreceptors and other cell types can be selectively activated by distinct stimulation frequencies in vitro. Yet, this principle still needs to be validated in humans in vivo. As a first step, this study explored the frequency preferences of human rods by means of transcorneal electrostimulation (TES), using the electrically-elicited pupillary responses (EEPRs) as an objective readout.

Evaluation of Local Rod and Cone Function in Stargardt Disease.

Purpose: In this study, chromatic pupil campimetry (CPC) was used to map local functional degenerative changes of cones and rods in Stargardt disease (STGD1).

Methods: 19 patients (age 36 ± 8 years; 12 males) with genetically confirmed ABCA4 mutations and a clinical diagnosis of STGD1 and 12 age-matched controls (age 37 ± 11 years; 2 males) underwent scotopic (rod-favoring) and photopic (cone-favoring) CPC. CPC evaluates the local retinal function in the central 30° visual field via analysis of the pupil constriction to local stimuli in a gaze-corrected manner.

Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes.

Usher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin-encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment.

Removal of RPE lipofuscin results in rescue from retinal degeneration in a mouse model of advanced Stargardt disease: Role of reactive oxygen species.

Accumulation of lipofuscin in the retinal pigment epithelium (RPE) is a hallmark of aging and is associated with retinal degeneration encountered in age-related macular degeneration (AMD) and Stargardt disease (SD). Currently, treatment for lipofuscin-induced retinal degeneration is unavailable. Here, we report that Remofuscin (INN: soraprazan, a tetrahydropyridoether small molecule) reverses lipofuscin accumulation in aged primary human RPE cells and is non-cytotoxic in aged SD mouse RPE cells in vitro.

Thickness-Varied Carbon Nanomembranes from Polycyclic Aromatic Hydrocarbons.

Despite the prospects of intrinsically porous planar nanomaterials in separation applications, their synthesis on a large scale remains challenging. In particular, preparing water-selective carbon nanomembranes (CNMs) from self-assembled monolayers (SAMs) is limited by the cost of epitaxial metal substrates and molecular precursors with specific chemical functionalities. In this work, we present a facile fabrication of CNMs from polycyclic aromatic hydrocarbons (PAHs) that are drop-cast onto arbitrary supports, including foils and metalized films.

How lesions at different locations along the visual pathway influence pupillary reactions to chromatic stimuli.

Purpose: To examine systematically how prechiasmal, chiasmal, and postchiasmal lesions along the visual pathway affect the respective pupillary responses to specific local monochromatic stimuli.

Methods: Chromatic pupil campimetry (CPC) was performed in three patient groups (10 subjects with status after anterior ischemic optic neuropathy, 6 with chiasmal lesions, and 12 with optic tract or occipital lobe lesions (tumor, ischemia)) using red, low-intensity red, and blue local stimuli within the central 30° visual field. Affected areas - as determined by visual field defects revealed using conventional static perimetry - were compared with non-affected areas.

Effect of central and peripheral cone- and rod-specific stimulation on the pupillary light reflex.

Purpose: To assess the effect of central and peripheral stimulation on the pupillary light reflex. The aim was to detect possible differences between cone- and rod-driven reactions.

Methods: Relative maximal pupil constriction amplitude (relMCA) and latency to constriction onset (latency) to cone- and rod-specific stimuli of 30 healthy participants (24 ± 5 years (standard deviation)) were measured using chromatic pupil campimetry.

An Optimized Treatment Protocol for Subretinal Injections Limits Intravitreal Vector Distribution.

Purpose: Subretinal injections (SRis) are commonly used in retinal gene therapy procedures to deliver adeno-associated virus (AAV) to photoreceptors and retinal pigment epithelial cells. We present an optimized surgical protocol to minimize off-target application of AAV in the vitreous, which in turn reduces the risk of extensive biodistribution and inflammation, ultimately leading to enhanced safety of the therapy.

Design: Experimental animal research study.

Longitudinal Evaluation of Hyper-Reflective Foci in the Retina Following Subretinal Delivery of Adeno-Associated Virus in Non-Human Primates.

Purpose: The purpose of this study was to evaluate whether clinical grade recombinant adeno-associated virus serotype 8 (rAAV8) leads to increased appearance of hyper-reflective foci (HRF) in the retina of non-human primates (NHPs) following subretinal gene therapy injection.

Methods: Different doses of rAAV8 vector (rAAV8. human phosphodiesterase 6A subunit (hPDE6A) at low dose: 1 × 1011 vector genomes (vg), medium dose: 5 × 1011 vg, or high dose: 1 × 1012 vg) were injected subretinally into the left eyes of NHPs in a formal toxicology study in preparation of a clinical trial.

Validity of the Pupillographic Sleepiness Test for the diagnosis of daytime sleepiness in children and adolescents and its relationship to sleepiness-associated outcomes.

Objectives: To report validation data for the Pupillographic Sleepiness Test (PST) in children and adolescents, evaluate its applicability for diagnosing excessive daytime sleepiness and its relationship to sleepiness-associated outcomes.

Methods: A cross-sectional diagnostic test accuracy study was performed. Patients underwent three PST at 9 a.

Three-year results of phase I retinal gene therapy trial for CNGA3-mutated achromatopsia: results of a non randomised controlled trial.

Aims: To 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).

Methods: Details of the study design have been previously described.

[Transcorneal electrostimulation in retinitis pigmentosa : Protocol of a multicentric prospective, randomized, controlled and double-masked trial on behalf of the Joint Federal Committee (G-BA pilot regulation)].

The focus of this large multicenter trial commissioned by the Joint Federal Committee (Gemeinsamer Bundesausschuss, G‑BA) is to determine a benefit of transcorneal electrical stimulation for retinitis pigmentosa (RP) patients. The main criterion for benefit is the kinetic visual field and whether the deterioration progresses more slowly in the study eyes compared to the sham-stimulated fellow eyes over a treatment period of 3 years.

Spatial and temporal resolution of the photoreceptors rescue dynamics after treatment with voretigene neparvovec.

Background: Voretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic mutations. In this study, we report on a novel and objective evaluation of a retinotopic photoreceptor rescue.

Methods: Seven eyes of five patients (14, 21, 23, 24, 36 years, 1 male, 4 females) with bi-allelic mutations have been treated with voretigene neparvovec.

Chromatic Pupil Campimetry Reveals Functional Defects in Exudative Age-Related Macular Degeneration with Differences Related to Disease Activity.

Purpose: The purpose of this study was to use chromatic pupil campimetry (CPC) for an objective evaluation of local retinal function in exudative age-related macular degeneration (AMD) and to assess disease activity.

Methods: Gaze-controlled CPC was performed in 19 subjects with optical coherence tomography-confirmed exudative AMD (75 ± 4 years; 11 women) and the results compared with those of an age-matched control group (n = 11; 72 ± 6 years; 8 women). Local retinal function was evaluated by measuring pupil responses to 3° red stimuli (60 cd/m, 1 second) at 41 positions covering 30° of the central visual field on a dim blue background (test duration 6 minutes).

Clinical Protocols for the Evaluation of Rod Function.

This work presents a quick clinical protocol for dark-adapted chromatic (DAC) perimetry as well as a novel clinical tool, scotopic chromatic pupil campimetry (CPC). The goal of the study was to explore the applicability of these methods in a clinical setting, their test-retest repeatability, and the congruence of the results. Local rod sensitivity was assessed at 36 locations within 30° eccentricity of the visual field in 15 healthy subjects (mean age 43 ± 16 years; 7 females and 8 males) with DAC perimetry (red and cyan stimuli) and CPC 2 times in repeated measurements.

Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial.

Importance: Achromatopsia linked to variations in the CNGA3 gene is associated with day blindness, poor visual acuity, photophobia, and involuntary eye movements owing to lack of cone photoreceptor function. No treatment is currently available.

Objective: To assess safety and vision outcomes of supplemental gene therapy with adeno-associated virus (AAV) encoding CNGA3 (AAV8.

Chromatic Full-Field Stimulus Threshold and Pupillography as Functional Markers for Late-Stage, Early-Onset Retinitis Pigmentosa Caused by Mutations.

Purpose: Mutations in the gene cause early-onset retinal degeneration (EORD). Clinical disease progression markers, such as visual fields or electrophysiology, are not reliably measurable in most patients to follow the retinal function in patients with -mutations.

Methods: Ten patients (five females, five males; age 22-56 years) with EORD caused by mutations were examined in a cross-sectional manner using best corrected visual acuity (BCVA), perimetry, full-field and multifocal electroretinography, full-field stimulus threshold (FST), and pupillography to red and blue light.