Short term morphological rescue of the fovea after gene therapy with voretigene neparvovec.

PURPOSE: Leber congenital amaurosis type 2 (LCA2) and early-onset severe retinal dystrophy (EOSRD) are linked to visual impairment with nyctalopia and visual acuity reduction in early childhood. In 2017, the first gene therapy voretigene neparvovec (Luxturna™) for patients with LCA and EOSRD cause by bi-allelic mutations in the RPE65 gene has been approved. Here we report on an example of short-term change in the foveal morphology after functionally successful gene therapy with voretigene neparvovec in a 15-year old patient. METHODS: The clinical examinations included best corrected visual acuity (BCVA), spectral domain optical coherence tomography (OCT) and adaptive optics retinal imaging. RESULTS: During follow-up over a period of 3 months after the treatment, an improvement of the central foveal morphology could be observed in OCT, with a clear demarcation of the external limiting membrane and changes in the photoreceptor mosaic on adaptive optics retinal imaging. These morphological rescue parameters correlated in part with the improvement in foveal-mediated vision after the treatment and adaptive optics imaging. Although the visual acuity improved only slightly at month 3, objective central cone evaluation with chromatic pupil campimetry showed an increase in the central sensitivity. In daily life, the patient reported her visional experience after the treatment as 'brighter'. CONCLUSION: Rapid changes in the correlates of photoreceptor morphology after successful gene therapy in patients with LCA/EORD can be quantifiable on individual level.

The Role and Views of Ophthalmologists During the COVID-19 Pandemic.

PURPOSE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic forced ophthalmologists to adjust their working conditions to ensure patient and staff safety, while still providing effective and timely treatment. This international survey among ophthalmologists was initiated to capture what actions ophthalmologists were taking and what their opinions were on the risks of infection in their workplace, the delay in treatment, the use of telemedicine and telephone for appointments, and the regional specifications and measures implemented by the respective authorities. METHODS: An open-source web tool was used to develop an online survey, to which ophthalmologists worldwide were invited via e-mail using international mailing lists (Media Mice, Singapore; Texere Publishing Inc, USA; CGO Gerling) and incentivized using a lottery. The physicians provided their level of agreement relating to the offered statements and gave free answers to the questions regarding the actions taken (conducted November 5th 2020 to December 20th 2020). RESULTS: After 91,000 invitations, responses were collected from 1122 ophthalmologists. Despite the use of large international mailing lists, mainly doctors from Europe participated. Half of the participants expressed great concern about possible SARS-CoV-2 infection in their patients. A significant number of younger ophthalmologists (≤50 years: 76.9%, n = 313; >50 years: 69.6%, n = 181) feared the delays that COVID-19 could cause to treatment. Reductions in patient numbers were broadly observed, with more ophthalmologists of younger age reporting greater declines. Nearly all ophthalmologists indicated that they provided disinfectant and the majority also used masks and questionnaires for screening. For 60.3% (n = 412) of ophthalmologists, telephone calls reduced the risk of 'no-shows'; 71.6% (n = 497) disagreed that telemedical evaluation is possible without slit lamp findings and fundus photos; and 57.0% of participants felt content with the governmental measures during the COVID-19 pandemic. CONCLUSION: The COVID-19 pandemic has significantly influenced the work of ophthalmologists. Based on the limited response rate, certain statements were only possible to evaluate for the European Union: with a noticeable reduction in patient numbers, delay in treatment was a major worry. Measures to protect and reassure patients should be undertaken, especially regarding those with vision-threatening diseases requiring treatment.

Vessel Evaluation in Patients with Primary Open-Angle Glaucoma, Normal Tension Glaucoma and Healthy Controls.

PURPOSE: To compare changes in central retinal arterial equivalent (CRAE), central retinal vein equivalent (CRVE), arteriovenous ratio (AVR), tortuosity and fractal dimension in primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG) and in a control group (CG) on fundus photographs. Further, to provide further evidence of vascular change in glaucoma patients using a novel method of tortuosity. PATIENTS AND METHODS: The primary endpoint was the change in CRAE, CRVE, AVR, fractal dimension and tortuosity of the retinal vasculature from baseline, retrospectively analyzed from 2011 to 2017 at the University Eye Hospital Tuebingen. Fundus photos of POAG (N = 49), NTG (N = 38) and CG (N = 18) were computer evaluated and analyzed in the quantities mentioned above. RESULTS: CRAE in NTG and POAG and CRVE in NTG significantly decreased (P = 0.02, P = 0.01; P = 0.03) whereas CRVE in POAG increased insignificantly (P = 0.72). In NTG, AVR decreased significantly (P = 0.05), but to a lesser extent than in POAG (P < 0.001). In CG, CRAE decreased insignificantly (P = 0.10), CRVE decreased significantly (P = 0.03) and AVR increased insignificantly (P = 0.77). In POAG tortuosity calculated using standard methods as well as our novel method, increased significantly (P = 0.015-0.04), whereas it did not occur in NTG (P = 0.18-0.57) and CG (P = 0.11-0.21). Fractal dimensions in POAG decreased significantly (P = 0.001-0.002), whereas in NTG and CG changes were insignificant (P = 0.33-0.92). CONCLUSION: Based on a retrospective analysis of fundus photographs, specific retinal vasculature features of the retinal vasculature display significant alterations associated with NTG and POAG. The assessment of tortuosity using our novel method was consistent with previously established methods for analyzing tortuosity.

Comparing Reading Speeds for Reading Standardized Single Sentences and Paragraphs in Patients with Maculopathy.

INTRODUCTION: The purpose of this study was to compare reading speeds (RS) of either paragraphs of text or single sentences in patients with maculopathy by investigating the repeatability of RS to decide which text type to use in studies on patients with maculopathy. METHODS: RS was measured for standardized texts in 25 participants with a central scotoma due to maculopathy (mean age 77.8 years ± 9.9 SD, mean binocular visual acuity 0.65 logMAR (±0.85 SD), median magnification requirement 3-fold). Reading 3 single sentences taken from the Radner reading charts (sample #1, #2, and #3) of 14 words and reading 3 paragraphs of International Reading Speed Texts (IReST, sample # 3, #6, and #10) with a mean of 132 (±3.2 SD) words, each in German, were compared. The 6 texts were read aloud in random order from a closed-circuit TV system, with size adjusted according to the individual magnification requirement. Reading time was measured by stopwatch, and speed was calculated in correctly read words per minute (wpm). Differences in RS depending on text length (single sentence vs. paragraph) and text sample were calculated by the Bland-Altman analysis. RESULTS: The mean RS showed no significant difference between 2 charts of the same kind (sentences: 93 wpm ± 37 SD; paragraphs: 95 wpm ± 38 SD). RS differences between 2 charts were lower in paragraphs than in single sentences. Highest correlations of RS between all 6 texts existed between the 3 IReST text samples (r = 0.98, 0.98, and 0.98) compared with the 3 Radner sentences (r = 0.89, 0.81, and 0.90). The inter-chart reliability (coefficient of repeatability) was smaller for the paragraphs (12.9 wpm) than for the single sentences (36.4 wpm). CONCLUSION: In patients with maculopathy, single sentences are well suited for single measurement of RS. For repeated measurements (e.g., monitoring the course of a reading disorder or assessing effects of interventions), paragraphs are preferable because of their lower variability of RS between the paragraphs.

CHANGES IN RETINAL SENSITIVITY AFTER GENE THERAPY IN CHOROIDEREMIA.

PURPOSE: Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). We evaluated retinal gene therapy with an adeno-associated virus vector that used to deliver a functional version of the CHM gene (AAV2-REP1). METHODS: THOR (NCT02671539) is a Phase 2, open-label, single-center, randomized study. Six male patients (51-60 years) with CHM received AAV2-REP1, by a single 0.1-mL subretinal injection of 10 genome particles during vitrectomy. Twelve-month data are reported. RESULTS: In study eyes, 4 patients experienced minor changes in best-corrected visual acuity (-4 to +1 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); one gained 17 letters and another lost 14 letters. Control eyes had changes of -2 to +4 letters. In 5/6 patients, improvements in mean (95% confidence intervals) retinal sensitivity (2.3 [4.0] dB), peak retinal sensitivity (2.8 [3.5] dB), and gaze fixation area (-36.1 [66.9] deg) were recorded. Changes in anatomical endpoints were similar between study and control eyes. Adverse events were consistent with the surgical procedure. CONCLUSION: Gene therapy with AAV2-REP1 can maintain, and in some cases, improve, visual acuity in CHM. Longer term follow-up is required to establish whether these benefits are maintained.

Efficacy and Safety of Retinal Gene Therapy Using Adeno-Associated Virus Vector for Patients With Choroideremia: A Randomized Clinical Trial.

IMPORTANCE: Choroideremia (CHM) is a rare, degenerative, genetic retinal disorder resulting from mutation of the CHM gene, leading to an absence of functional ras-associated binding escort protein 1 (REP1). There is currently no approved treatment for CHM. OBJECTIVE: To assess the safety and efficacy of retinal gene therapy with an adeno-associated virus vector (AAV2) designed to deliver a functional version of the CHM gene (AAV2-REP1) for treatment of patients with choroideremia. DESIGN, SETTING, AND PARTICIPANTS: Tübingen Choroideremia Gene Therapy (THOR) was a single-center, phase 2, open-label randomized clinical trial. Data were collected from January 11, 2016, to February 26, 2018. Twenty-four-month data are reported for 6 men with a molecularly confirmed diagnosis of CHM. Intention-to-treat analysis was used. INTERVENTIONS: Patients received AAV2-REP1 by a single, 0.1-mL subretinal injection of 1011 genome particles during vitrectomy into 1 eye randomly assigned to receive treatment. MAIN OUTCOMES AND MEASURES: Primary end point was change in best-corrected visual acuity (BCVA) on the Early Treatment Diabetic Retinopathy Study chart from baseline to month 24 in the treated eye vs the control eye. Secondary end points included microperimetry variables, change in fundus autofluorescence, and spectral-domain optical coherence tomographic evaluations from baseline to month 24 in the treated eye vs the control eye. RESULTS: On enrollment, the mean (SD) age of the 6 men included in the study was 54.9 (4.1) years. The mean (SD) BCVA score was 60.3 (13.4) (approximately 20/63 Snellen equivalent) in the study eyes and 69.3 (20.6) (approximately 20/40 Snellen equivalent) in the control eyes. At 24 months, the BCVA change was 3.7 (7.5) in the treated eyes and 0.0 (5.1) in the control eyes (difference, 3.7; 95% CI, -7.2 to 14.5; P = .43). Mean change in retinal sensitivity was 10.3 (5.5) dB in the treated eyes and 9.7 (4.9) dB in the control eyes (difference, 0.6; 95% CI, -10.2 to 11.4; P = .74). A total of 28 adverse events were reported; all were consistent with the surgical procedure (eg, conjunctival hyperemia, foreign body sensation), and none were regarded as severe. CONCLUSIONS AND RELEVANCE: Among 6 participants, gene therapy with AAV2-REP1 was associated with maintenance or improvement of visual acuity, although no significant difference was found from control eyes. All safety issues were associated with the surgical procedure and none were judged severe. Continued investigations could more precisely define the efficacy and safety of gene therapy with AAV2-REP1 in CHM. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02671539.