RNA gene editing in the eye and beyond: The neglected tool of the gene editing armatorium?

RNA editing allows correction of pathological point mutations without permanently altering genomic DNA. Theoretically targetable to any RNA type and site, its flexibility and reversibility makes it a potentially powerful gene editing tool. RNA editing offers a host of potential advantages in specific niches when compared to currently available alternative gene manipulation techniques.

MERTK missense variants in three patients with retinitis pigmentosa.

Background: is a transmembrane protein essential in regulating photoreceptor outer segment phagocytosis. Biallelic mutations in cause retinal degeneration. Here we present the retinal phenotype of three patients with missense variants in .

Phenotypic and Genetic Characteristics in a Cohort of Patients with Usher Genes.

Background: This study aimed to compare phenotype−genotype correlation in patients with Usher syndrome (USH) to those with autosomal recessive retinitis pigmentosa (NS-ARRP) caused by genes associated with Usher syndrome. Methods: Case notes of patients with USH or NS-ARRP and a molecularly confirmed diagnosis in genes associated with Usher syndrome were reviewed. Phenotypic information, including the age of ocular symptoms, hearing impairment, visual acuity, Goldmann visual fields, fundus autofluorescence (FAF) imaging and spectral domain optical coherence tomography (OCT) imaging, was reviewed.

Tamoxifen Retinopathy and Macular Telangiectasia Type 2: Similarities and Differences on Multimodal Retinal Imaging.

Purpose: Tamoxifen-induced retinopathy (TR) and macular telangiectasia type 2 (MacTel) share a highly similar retinal phenotype. In this study, we aimed to evaluate differences and similarities that may point toward underlying mechanisms linking both disease entities.

Design: Retrospective, cross sectional study.

Plasmid-mediated gene transfer of Cas9 induces vector-related but not SpCas9-related immune responses in human retinal pigment epithelial cells.

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) system represents a powerful gene-editing tool and could enable treatment of blinding diseases of the retina. As a peptide of bacterial origin, we investigated the immunogenic potential of Cas9 in models of retinal immunocompetent cells: human microglia (IMhu) and ARPE-19 cells. Transfection with Streptococcus pyogenes-Cas9 expression plasmids (SpCas9 plasmid) induced Cas9 protein expression in both cell lines.

Optogenetic approaches to therapy for inherited retinal degenerations.

Inherited retinal degenerations such as retinitis pigmentosa (RP) affect around one in 4000 people and are the leading cause of blindness in working age adults in several countries. In these typically monogenic conditions, there is progressive degeneration of photoreceptors; however, inner retinal neurons such as bipolar cells and ganglion cells remain largely structurally intact, even in end-stage disease. Therapeutic approaches aiming to stimulate these residual cells, independent of the underlying genetic cause, could potentially restore visual function in patients with advanced vision loss, and benefit many more patients than therapies directed at the specific gene implicated in each disorder.

CRISPR DNA Base Editing Strategies for Treating Retinitis Pigmentosa Caused by Mutations in .

Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerations and pathogenic variants in the () gene are major cause for autosomal dominant RP (adRP). Despite extensive attempts to treat -associated adRP, standardized curative treatment is still lacking. Recently developed base editors offer an exciting opportunity to correct pathogenic single nucleotide variants and are currently able to correct all transition variants and some transversion variants.

'It was like being hit with a brick': a qualitative study on the effect of clinicians' delivery of a diagnosis of eye disease for patients in primary and secondary care.

Objectives: To explore patients' experiences of getting a diagnosis of eye disease, the psychological impact of this and how this could be improved.

Design: An exploratory qualitative interview study using a narrative approach and inductive methods.

Setting: This study was conducted with patients who had attended ophthalmic appointments in primary and secondary care and in opticians located in the South of England.

A Network Meta-Analysis of Retreatment Rates following Bevacizumab, Ranibizumab, Aflibercept, and Laser for Retinopathy of Prematurity.

Topic: To compare bevacizumab, ranibizumab, aflibercept, and laser treatment as primary therapies for retinopathy of prematurity (ROP) in terms of retreatment rate.

Clinical Relevance: Anti-VEGF agents are increasingly used as primary treatment for ROP and may provide superior outcomes compared with laser in posterior disease. Head-to-head comparisons between different anti-VEGFs are lacking.

RNA-targeting strategies as a platform for ocular gene therapy.

Genetic medicine is offering hope as new therapies are emerging for many previously untreatable diseases. The eye is at the forefront of these advances, as exemplified by the approval of Luxturna® by the United States Food and Drug Administration (US FDA) in 2017 for the treatment of one form of Leber Congenital Amaurosis (LCA), an inherited blindness. Luxturna® was also the first in vivo human gene therapy to gain US FDA approval.

Rapid Quantification of the Binocular Visual Field for Clinical Trials: Performance of a Modified Esterman Supra-Threshold Test Implemented with the Open Perimetry Interface.

Purpose: We aimed to assess the performance of the modified-Esterman test (mET) as a rapid suprathreshold binocular quantification tool for the assessment of peripheral visual fields. The mET consists of an even spread of test points across the visual field.

Materials And Methods: The mET was implemented on the Octopus 0900 perimeter using the Open Perimetry Interface (OPI) and consisted of 160 points.

Variability of retinopathy consequent upon novel mutations in LAMA1.

Purpose: Bi-allelic mutations in LAMA1 (laminin 1) (OMIM # 150320) cause Poretti-Boltshauser Syndrome (PTBHS), a rare non-progressive cerebellar dysplasia disorder with ophthalmic manifestations including oculomotor apraxia, high myopia, and retinal dystrophy. Only 38 variants, nearly all loss of function have been reported. Here, we describe novel LAMA1 variants and detailed retinal manifestations in two unrelated families.

Visual function during and after an acute central serous chorioretinopathy episode.

Purpose: To evaluate visual function parameters during and after an acute central serous chorioretinopathy (CSC) episode.

Methods: A prospective study included 19 fovea involving acute CSC patients with episode resolution within 3 months from the episode onset. Optical coherence tomography, best corrected visual acuity (BCVA), contrast sensitivity (CS), microperimetry (MP), and multifocal electroretinography (mfERG) were performed at baseline, 3 and 6 months from the episode onset.

Morphological parameters predicting subthreshold micropulse laser effectiveness in central serous chorioretinopathy.

Purpose: The purpose of this prospective study was to predict the effectiveness of subthreshold micropulse laser (SML) based on morphological parameters in patients with central serous chorioretinopathy (CSC).

Methods: Thirty-one patients were examined at presentation, 3 months, and 6 months after the disease onset. In patients with persistent subretinal fluid (SRF) at 3 months, SML was performed.

Characterizing Visual Fields in RPGR Related Retinitis Pigmentosa Using Octopus Static-Automated Perimetry.

Purpose: Peripheral visual fields have not been as well defined by static automated perimetry as kinetic perimetry in RPGR-related retinitis pigmentosa. This study explores the pattern and sensitivities of peripheral visual fields, which may provide an important end point when assessing interventional clinical trials.

Methods: A retrospective observational cross-sectional study of 10 genetically confirmed RPGR subjects was performed.

Envisioning the development of a CRISPR-Cas mediated base editing strategy for a patient with a novel pathogenic single nucleotide variant.

Background: Inherited retinal degeneration (IRD) associated with mutations in the gene is associated with a severe, early-onset retinal degeneration for which no therapy currently exists. Base editing, with its capability to precisely catalyse permanent nucleobase conversion in a programmable manner, represents a novel therapeutic approach to targeting this autosomal recessive IRD, for which a gene supplementation is challenging due to the need to target three different retinal CRB1 isoforms.

Purpose: To report and classify a novel variant and envision a possible therapeutic approach in form of base editing.

[Sustainability in ophthalmology : Adaptation to the climate crisis and mitigation].

The climate crisis is threatening the health of current and future generations and represents a particular challenge for healthcare systems. To address man-made climate change, comprehensive adaptation and mitigation strategies are crucial. Medicine and ophthalmology offer various opportunities to reduce the CO (carbon dioxide) footprint - these should be implemented and politically encouraged.

Kinetics of Heterogeneous Background in Stargardt's Disease over Time.

Stargardt's disease (STGD1) is caused by mutations in the gene. Different lesions characterised by decreased autofluorescence levels are found in fundus autofluorescence (FAF) from STGD1 patients and could be used as outcome indicators for disease progression. We investigated the fate of foci with reduced autofluorescence (FRA) within the heterogeneous background of STGD1 patients using FAF imaging.

Challenges to Gene Editing Approaches in the Retina.

Retinal gene therapy has recently been at the cutting edge of clinical development in the diverse field of genetic therapies. The retina is an attractive target for genetic therapies such as gene editing due to the distinctive anatomical and immunological features of the eye, known as immune privilege, so that inherited retinal diseases (IRDs) have been studied in several clinical studies. Thus, rapid strides are being made toward developing targeted treatments for IRDs.