Extensive Macular Atrophy with Pseudodrusen-like appearance (EMAP): progression kinetics and late-stage findings.

PURPOSE: To describe the clinical outcome and late-stage findings of Extensive Macular Atrophy with Pseudodrusen-like appearance (EMAP). STUDY DESIGN: Retrospective cohort study. PARTICIPANTS: Seventy-eight patients (156 eyes) affected by EMAP. METHODS: We collected data on best-corrected visual acuity (BCVA), kinetic perimetry, optical coherence tomography (OCT), short-wavelength autofluorescence (SW-AF) and near-infrared autofluorescence (NIR-AF). Genetic testing for the TIMP3 and C1QTNF5 genes was performed via Sanger sequencing for 58 subjects, with no pathogenic variants identified. MAIN OUTCOME MEASURES: BCVA, visual field, and imaging findings at the last examination. Incidence rates and time-to-event curves for blindness with the United States Social Security Administration (US-SSA) and World Health Organization (WHO) criteria, foveal involvement, and atrophy enlargement beyond the 30° and 55° field of view. RESULTS: At the most recent visit, the mean age was 70.9 ± 5.2 years. 58.1% of the patients were blind with the US criteria, and 25.8% according to the WHO. All eyes had large central scotomas, in 22.7% of the cases associated with visual field constriction. We detected focal openings or large dehiscences of the Bruch's membrane in 25.4% of the eyes. NIR-AF shows increased visibility of the choroidal vessels beyond the atrophy in 87.2% of the eyes. The incidence rates for blindness were 3.95/100-subjects-year with the US criteria and 1.54/100-subjects-year according to the WHO. The incidence rates were 22.8/100-eye-year for foveal involvement, 12.0/100-eye-year for atrophy enlargement beyond the 30° and 6.6/100-eye-year for atrophy enlargement beyond 55°. The estimates were not influenced by the age of onset. CONCLUSION: We identified characteristic imaging findings, including Bruch's membrane ruptures, in elder EMAP patients and calculated incidence rates for different functional and anatomical outcomes.

Coding and non-coding variants in the ciliopathy gene CFAP410 cause early-onset non-syndromic retinal degeneration.

Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. The implementation of next-generation sequencing in routine diagnostics, together with advanced clinical phenotyping including multimodal retinal imaging, have contributed to the increase of reports describing novel genotype-phenotype associations and phenotypic expansions. In this study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with syndromic recessive Jeune syndrome. The most common retinal phenotypes were cone-rod and rod-cone dystrophies, but the clinical presentations were unified by their early onset as well as the severe impact on central visual function. Twelve variants were detected (three pathogenic, seven likely pathogenic, two of uncertain significance), eight of which were novel. One deep intronic change, c.373+91A>G, led to the creation of a cryptic splice acceptor site in intron four, followed by the inclusion of a 200- base pair pseudoexon and subsequent premature stop codon formation. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Meta-analysis of all published and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.

ATXN7-Related Cone-Rod Dystrophy: The Integrated Functional Evaluation of the Cerebellum (CERMOI) Study.

Importance: Reliable biomarkers with diagnostic and prognostic values are needed for upcoming gene therapy trials for spinocerebellar ataxias. Objective: To identify ophthalmological biomarkers in a sample of spinocerebellar ataxia type 7 (SCA7) carriers. Design, Setting, and Participants: This article presents baseline data from a cross-sectional natural history study conducted in Paris, France, reference centers for rare diseases from May 2020 to April 2021. Data were analyzed from September to December 2022. Fifteen adult ATXN7 pathogenic expansion carriers (9 with preataxia and 6 with ataxia) were included, all with a Scale for the Assessment and Rating of Ataxia (SARA) score of 15 of 40 or lower. Patients were recruited at the Paris Brain Institute, and all contacted patients accepted to participate in the study. Main Outcomes and Measures: Three visits (baseline, 6 months, and 12 months) were planned, including neurological examination (SARA and Composite Cerebellar Functional Severity Score), ophthalmological examination (best-corrected visual acuity, microperimetry, full-field electroretinogram, optical coherence tomography, and fundus autofluorescence imaging), and neurofilament light chain (NfL) measurements. Here we report the baseline ophthalmic data from the cohort and determine whether there is a correlation between disease scores and ophthalmic results. Results: Among the 15 included SCA7 carriers (median [range] age, 38 [18-60] years; 8 women and 7 men), 12 displayed cone or cone-rod dystrophy, with the number of CAG repeats correlating with disease severity (ρ, 0.73, 95% CI, 0.34 to 0.90; P < .001). Two patients with cone-rod dystrophy exhibited higher repeat numbers and greater ataxia scores (median [range] SARA score, 9 [7-15]) compared to those with only cone dystrophy (median [range] SARA score, 2 [0-5]). A correlation emerged for outer nuclear layer thickness with SARA score (ρ, -0.88; 95% CI, -0.96 to -0.59; P < .001) and NfL levels (ρ, -0.87; 95% CI, -0.86 to 0.96; P < .001). Moreover, ataxia severity was correlated with visual acuity (ρ: 0.89; 95% CI, 0.68 to 0.96; P < .001) and retinal sensitivity (ρ, -0.88; 95% CI, -0.96 to 0.59; P < .001). Conclusions and Relevance: In this cross-sectional study, retinal abnormalities were found at preataxic stages of the disease. Most of the carriers presented with cone dystrophy and preserved rod function. The outer nuclear layer thickness correlated with SARA score and plasma NfL levels suggesting nuclear layer thickness to be a biomarker of disease severity. These findings contribute to understanding the dynamics of SCA7-related retinal dystrophy and may help lay the groundwork for future therapeutic intervention monitoring and clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04288128.

Variants in UBAP1L lead to autosomal recessive rod-cone and cone-rod dystrophy.

PURPOSE: Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent. METHODS: Genome, targeted next-generation, and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium cells, and zebrafish. Variants' pathogenicity was accessed using 3D-modeling and/or ROs. RESULTS: Here, we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in 4 independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the retinal pigment epithelium and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin-associated domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the solenoid of overlapping ubiquitin-associated domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein. CONCLUSION: Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population.

Real-World Safety and Effectiveness of Voretigene Neparvovec: Results up to 2 Years from the Prospective, Registry-Based PERCEIVE Study.

Voretigene neparvovec (VN) is the first available gene therapy for patients with biallelic RPE65-mediated inherited retinal dystrophy who have sufficient viable retinal cells. PERCEIVE is an ongoing, post-authorization, prospective, multicenter, registry-based observational study and is the largest study assessing the real-world, long-term safety and effectiveness of VN. Here, we present the outcomes of 103 patients treated with VN according to local prescribing information. The mean (SD) age was 19.5 (10.85) years, 52 (50.5%) were female, and the mean (SD) duration of the follow up was 0.8 (0.64) years (maximum: 2.3 years). Thirty-five patients (34%) experienced ocular treatment-emergent adverse events (TEAEs), most frequently related to chorioretinal atrophy (n = 13 [12.6%]). Eighteen patients (17.5%; 24 eyes [13.1%]) experienced ocular TEAEs of special interest, including intraocular inflammation and/or infection related to the procedure (n = 7). The mean (SD) changes from baseline in full-field light-sensitivity threshold testing (white light) at month 1, month 6, year 1, and year 2 were -16.59 (13.48) dB (51 eyes), -18.24 (14.62) dB (42 eyes), -15.84 (14.10) dB (10 eyes), and -13.67 (22.62) dB (13 eyes), respectively. The change in visual acuity from baseline was not clinically significant. Overall, the outcomes of the PERCEIVE study are consistent with the findings of VN pivotal clinical trials.

Development and Validation of a Novel Mobility Test for Rod-Cone Dystrophies: From Reality to Virtual Reality.

PURPOSE: To validate a novel mobility test (MOST, MObility Standardized Test) and performance outcomes in real (RL) and virtual (VR) environments to be used for interventional clinical studies in order to characterize vision impairment in rod-cone dystrophies, also known as retinitis pigmentosa (RP). DESIGN: Prospective, interventional, noninvasive, reliability and validity analysis. METHODS: We designed MOST to be used in both VR and RL and conducted 3 experimental studies with 89 participants to (1) validate the difficulty of the mobility courses (15 controls), (2) determine the optimal number of light levels and training trials (14 participants with RP), and (3) validate the reproducibility (test-retest), reliability (VR/RL), sensitivity, and construct/content validity of the test (30 participants with RP and 30 controls). A comprehensive ophthalmologic examination was performed in all subjects. Outcomes of interest included MOST performance score, visual acuity, contrast sensitivity, dark adaptation thresholds, visual field parameters, and correlation between the performance score and visual function. RESULTS: The mobility courses exhibited statistically similar difficulty, and 5 trials are sufficient to control for the learning effect. MOST is highly reproducible (test-retest correlations >0.98) and reliable (correlations VR/RL = 0.98). MOST achieved a discrimination between participants with RP and controls (accuracy >95%) and between early and late stages of the disease (82.3% accuracy). The performance score is correlated with visual function parameter (0.57-0.94). CONCLUSION: MOST is a validated mobility test, with the controlled learning effect, excellent reproducibility, and high agreement between RL and VR conditions, as well as sensitivity and specificity to measure disease progression and therapeutic benefit in rod-cone dystrophies.

Functional Vision in Patients With Biallelic USH2A Variants.

PURPOSE: To describe functional vision (FV) and investigate the relationship between FV, visual acuity (VA), and hill of vision (VTOT) at baseline in patients with biallelic USH2A variants. DESIGN: Multicenter, international, cross-sectional study. METHODS: In individuals with biallelic disease-causing variants in USH2A, clinical diagnosis of Usher syndrome type 2 (USH2) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) was based on history of hearing loss and audiology examinations. The VALVVFQ-48 was administered verbally to participants ≥18 years old. VA was measured in both eyes; VTOT was determined from static perimetry in the study eye (better VA). FV scores were calculated using Rasch analysis. RESULTS: Median age of 121 participants (76 with USH2, 45 with ARRP) was 41 years (range: 19-80); 54% were female. FV scores varied from -2.0 to 7.6 logits (median [interquartile range (IQR)]: 2.8 [1.5-3.8]). ARRP and USH2 participants had similar FV scores, both before [mean (95% CI): 2.8 (2.3-3.4) and 2.7 (2.3-3.2), respectively], and after [mean (95% CI): 2.5 (2.1-3.0) and 2.9 (2.6-3.3), respectively; P = .24] adjusting for age, VA, disease duration, and VTOT. VA and VTOT accounted for 29% and 26% of the variance in FV scores, respectively (P < .001 for each). Together, they accounted for 36% of variance observed. CONCLUSIONS: Biallelic USH2A variants were associated with a large range of FV, yet similar in ARRP and USH2, despite hearing loss in USH2. The modified VALVVFQ-48 we evaluated is not ideal for detecting the impact of USH2A-associated retinal degenerations on activities of daily living.

The Extraordinary Phenotypic and Genetic Variability of Retinal and Macular Degenerations: The Relevance to Therapeutic Developments.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of rare conditions leading to various degrees of visual handicap and to progressive blindness in more severe cases. Besides visual rehabilitation, educational, and socio-professional support, there are currently limited therapeutic options, but the approval of the first gene therapy product for RPE65-related IRDs raised hope for therapeutic innovations. Such developments are facing obstacles intrinsic to the disease and the affected tissue including the extreme phenotypic and genetic variability of IRDs and the fine tuning of visual processing through the complex architecture of the postmitotic neural retina. A precise phenotypic characterization is required prior to genetic testing, which now relies on high-throughput sequencing. Their challenges will be discussed within this article as well as their implications in clinical trial design.

Interface self-referenced dynamic full-field optical coherence tomography.

Dynamic full-field optical coherence tomography (D-FFOCT) has recently emerged as an invaluable live label-free and non-invasive imaging modality able to image subcellular biological structures and their metabolic activity within complex 3D samples. However, D-FFOCT suffers from fringe artefacts when imaging near reflective surfaces and is highly sensitive to vibrations. Here, we present interface Self-Referenced (iSR) D-FFOCT, an alternative configuration to D-FFOCT that takes advantage of the presence of the sample coverslip in between the sample and the objective by using it as a defocused reference arm, thus avoiding the aforementioned artefacts. We demonstrate the ability of iSR D-FFOCT to image 2D fibroblast cell cultures, which are among the flattest mammalian cells.

Qualitative exploration of the visual function impairments and impacts on vision-dependent activities of daily living in Retinitis Pigmentosa and Leber Congenital Amaurosis: content validation of the ViSIO-PRO and ViSIO-ObsRO measures.

BACKGROUND: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The associated visual impairments have significant impacts on patients' vision-dependent activities of daily living (ADL), mobility, and distal health-related quality of life (HRQoL). To adequately capture patient and caregiver perspectives in clinical trials, patient and observer-reported outcome instruments must demonstrate sufficient evidence of content validity in the target population. This study aimed to explore the patient experience of RP/LCA and assess the content validity of the Visual Symptom and Impact Outcomes PRO (ViSIO-PRO) and ObsRO (ViSIO-ObsRO) instruments in RP/LCA. METHODS: A total of 66 qualitative, combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted (33 adults, 10 adolescents, 8 children and 15 caregivers of children) in the US, France, Germany, and Canada. Patients had a clinical and genetic diagnosis of RP/LCA from a range of genotypes. CE results were used to further inform the development of a conceptual model and CD interviews assessed the relevance and understanding of the 44-item ViSIO-PRO and 26-item ViSIO-ObsRO instruments. Interviews were conducted across two iterative rounds to allow item modifications. RESULTS: Findings were consistent across RP/LCA genotypes. Night blindness, reduced peripheral vision, vision in very bright lighting and light/dark adaptation were the most frequently reported visual function symptoms impacting vision-dependent ADL and mobility. Impacts on distal HRQoL domains were also reported. The ViSIO-PRO and ObsRO items were well understood by participants and relevant across genotypes. The instructions, 7-day recall period and response scales were well understood and endorsed. Participant and expert clinician feedback supported modifications to item wording, the addition of six new ViSIO-PRO items and one new ViSIO-ObsRO item, and the removal of one ViSIO-PRO item due to lack of relevance. CONCLUSIONS: Findings support the content validity of the ViSIO-PRO and ViSIO-ObsRO instruments for use across RP/LCA genotypes. Ongoing research to evaluate the psychometric validity of the instruments will support future use of the instruments as efficacy endpoints in clinical trials and in general clinical practice to track disease severity and impact of disease on functioning.

Generation of gene corrected human isogenic iPSC lines (IDVi003-A_CR13, IDVi003-A_CR21, IDVi003-A_CR24) from an inherited retinal dystrophy patient-derived IPSC line ITM2B-5286-3 (IDVi003-A) carrying the ITM2B c.782A > C variant using CRISPR/Cas9.

The ITM2B-related retinal dystrophy (ITM2B-RD) was identified within patients carrying the autosomal dominant variant [c.782A > C, p.(Glu261Ala)] in ITM2B from whom induced pluripotent stem cell (IPSC) lines were previously generated. Here, we report the generation of three isogenic control iPSC lines from the derived affected subject cell line (ITM2B-5286-3) using CRISPR/Cas9 engineering. The three generated lines express pluripotency markers, can be differentiated into the three germ layers and present a normal karyotype. The generated iPSC lines can be used to study the implications of ITM2B-RD variant in vitro.

Development of Novel Patient-Reported Outcome (PRO) and Observer-Reported Outcome (ObsRO) Instruments in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA): ViSIO-PRO and ViSIO-ObsRO.

INTRODUCTION: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are rare inherited retinal degenerative disorders resulting in visual impairments and impacts on patients' vision-dependent activities of daily living (ADL), mobility and distal health-related quality of life (HRQoL). This study aimed to conduct qualitative research to understand the patient experience of RP/LCA across genotypes and inform development of patient- and observer-reported outcome (PRO/ObsRO) instruments in RP/LCA. METHODS: Research activities included a qualitative literature review and review of existing visual function PRO instruments in RLBP1 RP, and concept elicitation (CE) and cognitive debriefing (CD) interviews of existing PRO instruments with patients with RLBP1 RP, expert clinicians, and payers. In wider RP/LCA, a social media listening (SML) study and a qualitative literature review was conducted, while psychometric evaluation of a PRO instrument in LCA was performed. Input from expert clinicians was sought at key stages. RESULTS: Findings from the qualitative literature reviews identified a range of visual function symptoms which had significant impacts on patients' vision-related ADL and distal HRQoL. Patient interviews identified additional visual function symptoms and impacts not previously reported in published literature. These sources informed development and refinement of a conceptual model displaying the patient experience of RP/LCA. Review of existing visual function PRO instruments, and CD interviews evaluating their content validity, confirmed that no existing instrument provides a comprehensive assessment of all concepts relevant to patients with RP/LCA. This highlighted the need for development of the Visual Symptom and Impact Outcomes PRO and ObsRO instruments to adequately assess the patient experience of RP/LCA. CONCLUSIONS: Results informed and supported development of the instruments to assess visual functioning symptoms and vision-dependent ADL, mobility and distal HRQoL in RP/LCA, in accordance with regulatory standards. Next steps to further support use in RP/LCA clinical trials/practice includes content and psychometric validation of the instruments in this population.

Change in Cone Structure Over 24 Months in USH2A-Related Retinal Degeneration.

PURPOSE: To describe cone structure changes using adaptive optics scanning laser ophthalmoscopy (AOSLO) in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) study. DESIGN: Multicenter, longitudinal natural history study. METHODS: AOSLO images were acquired at 4 centers, twice at baseline and annually for 24 months in this natural history study. For each eye, at least 10 regions of interest (ROIs) with ≥50 contiguous cones were analyzed by masked, independent graders. Cone spacing Z-scores, standard deviations from the normal mean at the measured location, were compared between graders and tests at baseline. The association of cone spacing with clinical characteristics was assessed using linear mixed effects regression models weighted by image quality score. Annual rates of change were calculated based on differences between visits. RESULTS: Fourteen eyes of 14 participants were imaged, with 192 ROIs selected at baseline. There was variability among graders, which was greater in images with lower image quality score (P < .001). Cone spacing was significantly correlated with eccentricity, quality score, and disease duration (P < .02). On average, the cone spacing Z-score increased 0.14 annually (about 9%, P < .001). We observed no significant differences in rate of change between disease type (Usher syndrome or retinitis pigmentosa), imaging site, or grader. CONCLUSIONS: Using current methods, the analysis of quantitative measures of cone structure showed some challenges, yet showed promise that AOSLO images can be used to characterize progressive change over 24 months. Additional multicenter studies using AOSLO are needed to advance cone mosaic metrics as sensitive outcome measures for clinical trials. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Progression of Stargardt Disease as Determined by Fundus Autofluorescence Over a 24-Month Period (ProgStar Report No. 17).

PURPOSE: To estimate the progression rate of atrophic lesions in Stargardt disease derived from fundus autofluorescence (FAF). DESIGN: International, multicenter, prospective cohort study. METHODS: A total of 259 participants aged ≥6 years with disease-causing variants in the ABCA4 gene were enrolled from 9 centers and followed over a 24-month period. FAF images were obtained every 6 months, and areas of definitely decreased autofluorescence (DDAF) and decreased autofluorescence (DAF) were quantified. Progression rates were estimated from linear mixed models with time as the independent variable. RESULTS: A total of 488 study eyes of 259 participants (88.8% with both eyes) were enrolled and images from 432 eyes were followed for 24 months. The overall estimated progression of DDAF was 0.74 mm2/y (95% CI 0.64-0.85, P < .0001) and that of DAF was 0.64 mm2/y (95% CI 0.57-0.71) over a 24-month period in univariate analysis. Growth rates were strongly dependent on baseline lesion area. After square root transformation, the DDAF growth rate was not dependent on baseline lesion radius (P = .11), whereas the DAF growth rate was dependent (P < .0001). Genotype was not found to significantly impact the growth rate of DDAF or DAF lesions. CONCLUSIONS: FAF may serve as a convenient monitoring tool and suitable end point for interventional clinical trials that aim to slow disease progression. DDAF and DAF lesion sizes at baseline are strong predicting factors for lesion area growth and can be partially accounted for by square root transformation.

Psychometric Validation of the ViSIO-PRO and ViSIO-ObsRO in Retinitis Pigmentosa and Leber Congenital Amaurosis.

INTRODUCTION: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The Visual Symptom and Impact Outcomes patient-reported outcome (ViSIO-PRO) and observer-reported outcome (ViSIO-ObsRO) instruments were developed in this population to assess visual function symptoms and impacts on vision-dependent activities of daily living (ADL) and distal health-related quality of life (HRQoL). This study aimed to explore the psychometric properties of the ViSIO-PRO and ViSIO-ObsRO in RP/LCA. METHODS: The 49-item ViSIO-PRO and 27-item ViSIO-ObsRO instruments were completed by 83 adult and adolescent patients and 22 caregivers of child patients aged 3-11 years with RP/LCA, respectively, at baseline and 12-16-day follow-up. Concurrent measures were also administered at baseline. Psychometric analyses assessed item (question) properties, dimensionality, scoring, reliability, validity, and score interpretation. RESULTS: Item responses were mainly evenly distributed across the response scale, and inter-item correlations were mostly moderate to strong (> 0.30) at baseline within hypothesized domains. Item deletion was informed by item properties, qualitative data, and clinical input and supported retention of 35 ViSIO-PRO items and 25 ViSIO-ObsRO items. Confirmatory factor analysis in line with pre-hypothesized domains supported a four-factor model assessing visual function symptoms, mobility, vision-dependent ADL, and distal HRQoL. A bifactor model supported calculation of total scores and four domain scores. Internal consistency was high for domain and total scores (Cronbach's alpha > 0.70) and test-retest reliability for total scores was strong between baseline and 12-16-day follow-up (intraclass correlation coefficients 0.66-0.98). Convergent validity was supported by strong correlations in a logical pattern with concurrent measures. Mean baseline scores differed significantly between severity groups. Distribution-based methods provided initial insights to guide interpretation of scores. CONCLUSIONS: Findings supported item reduction and established scoring of the instruments. Evidence of reliability and validity as outcome measures in RP/LCA was also reported. Further research is ongoing to explore responsiveness of the ViSIO-PRO and ViSIO-ObsRO instruments and interpretation of change scores.

Shedding light on myopia by studying complete congenital stationary night blindness.

Myopia is the most common eye disorder, caused by heterogeneous genetic and environmental factors. Rare progressive and stationary inherited retinal disorders are often associated with high myopia. Genes implicated in myopia encode proteins involved in a variety of biological processes including eye morphogenesis, extracellular matrix organization, visual perception, circadian rhythms, and retinal signaling. Differentially expressed genes (DEGs) identified in animal models mimicking myopia are helpful in suggesting candidate genes implicated in human myopia. Complete congenital stationary night blindness (cCSNB) in humans and animal models represents an ON-bipolar cell signal transmission defect and is also associated with high myopia. Thus, it represents also an interesting model to identify myopia-related genes, as well as disease mechanisms. While the origin of night blindness is molecularly well established, further research is needed to elucidate the mechanisms of myopia development in subjects with cCSNB. Using whole transcriptome analysis on three different mouse models of cCSNB (in Gpr179-/-, Lrit3-/- and Grm6-/-), we identified novel actors of the retinal signaling cascade, which are also novel candidate genes for myopia. Meta-analysis of our transcriptomic data with published transcriptomic databases and genome-wide association studies from myopia cases led us to propose new biological/cellular processes/mechanisms potentially at the origin of myopia in cCSNB subjects. The results provide a foundation to guide the development of pharmacological myopia therapies.

RNA-based therapies in inherited retinal diseases.

Inherited retinal diseases (IRDs) are a genetically and phenotypically heterogeneous group of genetic eye disorders. There are more than 300 disease entities, and together this group of disorders affects millions of people globally and is a frequent cause of blindness or low-vision certification. However, each type is rare or ultra-rare. Characteristically, the impaired vision in IRDs is due to retinal photoreceptor dysfunction and loss resulting from mutation in a gene that codes for a retinal protein. Historically, IRDs have been considered incurable and individuals living with these blinding conditions could be offered only supportive care. However, the treatment landscape for IRDs is beginning to evolve. Progress is being made, driven by improvements in understanding of genotype-phenotype relationships, through advances in molecular genetic testing and retinal imaging. Alongside this expanding knowledge of IRDs, the current era of precision medicine is fueling a growth in targeted therapies. This has resulted in the first treatment for an IRD being approved. Several other therapies are currently in development in the IRD space, including RNA-based therapies, gene-based therapies (such as augmentation therapy and gene editing), cell therapy, visual prosthetics, and optogenetics. RNA-based therapies are a novel approach within precision medicine that have demonstrated success, particularly in rare diseases. Three antisense oligonucleotides (AONs) are currently in development for the treatment of specific IRD subtypes. These RNA-based therapies bring several key advantages in the setting of IRDs, and the potential to bring meaningful vision benefit to individuals living with inherited blinding disorders. This review will examine the increasing breadth and relevance of RNA-based therapies in clinical medicine, explore the key features that make AONs suitable for treating genetic eye diseases, and provide an overview of the three-leading investigational AONs in clinical trials.

Association of Missense Variants in VSX2 With a Peculiar Form of Congenital Stationary Night Blindness Affecting All Bipolar Cells.

Importance: Congenital stationary night blindness (CSNB) is an inherited stationary retinal disorder that is clinically and genetically heterogeneous. To date, the genetic association between some cases with CSNB and an unusual complex clinical picture is unclear. Objective: To describe an unreported CSNB phenotype and the associated gene defect in 3 patients from 2 unrelated families. Design, Setting, and Participants: This retrospective case series was conducted in 2021 and 2022 at a national referral center for rare ocular diseases. Data for 3 patients from a cohort of 140 genetically unsolved CSNB cases were analyzed clinically and genetically. Exposures: Complete ocular examination including full-field electroretinography and multimodal fundus imaging (spectral-domain optical coherence tomography, color, infrared reflectance, and short-wavelength autofluorescence photographs) were performed. The gene defect was identified by exome sequencing and confirmed by Sanger sequencing and co-segregation analysis in 1 family. Screening was performed for genetically unsolved CSNB cases for VSX2 variants by direct Sanger sequencing. Main Outcomes and Measures: Ocular and molecular biology findings. Results: The series included 3 patients whose clinical investigations occurred at ages in the early 30s, younger than 12 years, and in the mid 40s. They had nystagmus, low stable visual acuity, and myopia from birth and experienced night blindness. Two older patients had bilateral lens luxation and underwent lens extraction. Full-field electroretinography revealed an electronegative Schubert-Bornschein appearance, combining characteristics of incomplete and complete CSNB, affecting the function of rod and cone ON- and OFF-bipolar cells. Exome sequencing and co-segregation analysis in a consanguineous family with 2 affected members identified a homozygous variant in VSX2. Subsequently, screening of the CSNB cohort identified another unrelated patient harboring a distinct VSX2 variant. Conclusions and Relevance: This case series revealed a peculiar pan-bipolar cell retinopathy with lens luxation associated with variants in VSX2. Clinicians should be aware of this association and VSX2 added to CSNB diagnostic gene panels.

Baseline Microperimetry and OCT in the RUSH2A Study: Structure-Function Association and Correlation With Disease Severity.

PURPOSE: To investigate baseline mesopic microperimetry (MP) and spectral domain optical coherence tomography (OCT) in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study. DESIGN: Natural history study METHODS: Setting: 16 clinical sites in Europe and North AmericaStudy Population: Participants with Usher syndrome type 2 (USH2) (N = 80) or autosomal recessive nonsyndromic RP (ARRP) (N = 47) associated with biallelic disease-causing sequence variants in USH2AObservation Procedures: General linear models were used to assess characteristics including disease duration, MP mean sensitivity and OCT intact ellipsoid zone (EZ) area. The associations between mean sensitivity and EZ area with other measures, including best corrected visual acuity (BCVA) and central subfield thickness (CST) within the central 1 mm, were assessed using Spearman correlation coefficients. MAIN OUTCOME MEASURES: Mean sensitivity on MP; EZ area and CST on OCT. RESULTS: All participants (N = 127) had OCT, while MP was obtained at selected sites (N = 93). Participants with Usher syndrome type 2 (USH2, N = 80) and nonsyndromic autosomal recessive Retinitis Pigmentosa (ARRP, N = 47) had the following similar measurements: EZ area (median (interquartile range [IQR]): 1.4 (0.4, 3.1) mm2 vs 2.3 (0.7, 5.7) mm2) and CST (median (IQR): 247 (223, 280) µm vs 261 (246, 288), and mean sensitivity (median (IQR): 3.5 (2.1, 8.4) dB vs 5.1 (2.9, 9.0) dB). Longer disease duration was associated with smaller EZ area (P < 0.001) and lower mean sensitivity (P = 0.01). Better BCVA, larger EZ area, and larger CST were correlated with greater mean sensitivity (r > 0.3 and P < 0.01). Better BCVA and larger CST were associated with larger EZ area (r > 0.6 and P < 0.001). CONCLUSIONS: Longer disease duration correlated with more severe retinal structure and function abnormalities, and there were associations between MP and OCT metrics. Monitoring changes in retinal structure-function relationships during disease progression will provide important insights into disease mechanism in USH2A-related retinal degeneration.