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Congenital ocular malformations originate from defective morphogenesis during early eye development and cause 25% of childhood blindness. Formation of the eye is a multi-step, dynamic process; it involves evagination of the optic vesicle, followed by distal and ventral invagination, leading to the formation of a two-layered optic cup with a transient optic fissure. These tissue folding events require extensive changes in cell shape and tissue growth mediated by cytoskeleton mechanics and intercellular adhesion. We hypothesized that the Rho GTPase Cdc42 may be an essential, convergent effector downstream of key regulatory factors required for ocular morphogenesis. CDC42 controls actin remodeling, apicobasal polarity, and junction assembly. Here we identify a novel essential function for Cdc42 during eye morphogenesis in mouse; in Cdc42 mutant eyes expansion of the ventral optic cup is arrested, resulting in microphthalmia and a wide coloboma. Our analyses show that Cdc42 is required for expression of the polarity effector proteins PRKCZ and PARD6, intercellular junction protein tight junction protein 1, β -catenin, actin cytoskeleton F-actin, and contractile protein phospho myosin light chain 2. Expression of RPE fate determinants OTX2 and MITF, and formation of the RPE layer are severely affected in the temporal domain of the proximal optic cup. EdU incorporation is significantly downregulated. In addition, mitotic retinal progenitor cells mislocalize deeper, basal regions, likely contributing to decreased proliferation. We propose that morphogenesis of the ventral optic cup requires Cdc42 function for coordinated optic cup expansion and establishment of subretinal space, tissue tension, and differentiation of the ventral RPE layer. [ABSTRACT FROM AUTHOR]

Retinal ganglion cells (RGCs) are crucial for vision, and they interact across species with broadly conserved cell types that include neural partners, astrocytes, and microglia in the retina and the brain. Humans have approximately half as many ganglion cell types as mice, and human high-acuity vision relies on only a few RGC types within the fovea, a structure that is absent in mice. RGCs communicate with microglia and astrocytes to impact glial biology, and glial cells in turn modulate ganglion cell connectivity and function. Emerging models for studying the human visual system may uncover human-specific differences in neural development and neuron–glia interactions that may drive specialized features of human brain development more broadly. Retinal ganglion cells (RGCs) are the brain's gateway for vision, and their degeneration underlies several blinding diseases. RGCs interact with other neuronal cell types, microglia, and astrocytes in the retina and in the brain. Much knowledge has been gained about RGCs and glia from mice and other model organisms, often with the assumption that certain aspects of their biology may be conserved in humans. However, RGCs vary considerably between species, which could affect how they interact with their neuronal and glial partners. This review details which RGC and glial features are conserved between mice, humans, and primates, and which differ. We also discuss experimental approaches for studying human and primate RGCs. These strategies will help to bridge the gap between rodent and human RGC studies and increase study translatability to guide future therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: Neovascular age-related macular degeneration (nAMD) is the leading cause of irreversible vision loss in developed countries. However, a significant gap persists in understanding this population, exacerbated by their advanced age and visual impairments, which can hinder research participation and access to healthcare. The purpose of this study was to describe the content of the questionnaire and the participating patients with nAMD. Methods: The survey includes patients diagnosed with nAMD who had previously received treatment or were currently undergoing intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Participants were recruited using various methods, as reaching out to patients who are no longer receiving treatment poses a particular challenge. A patient and public advisory board assisted throughout the study period. Results: Of the 713 electronic invitations sent out, 494 (69.3%) patients responded to the questionnaire, with an additional 57 responses obtained through e-mail or telephone interviews. Due to the exclusion of 16 responses, there were a total of 535 valid responses, including 176 from patients previously treated and 359 from those currently undergoing treatment for nAMD. The median age of respondents was 79.9 years (interquartile range [IQR] 75.5–84.7), with 59.8% being women. Among them, 53.2% were married, while 43.1% lived alone. Conclusions: Data from the I-OPTA (Identification of Patient-Reported Barriers in Treatment for nAMD) questionnaire allows future exploration of patients who are no longer receiving treatment, patients' knowledge about preventive measures, and the impact of nAMD on visual function and quality of life. Future research, including studies that integrate data from corresponding retinal images and Danish national registers, has the potential to generate invaluable knowledge, providing benefits to both patients and healthcare professionals. [ABSTRACT FROM AUTHOR]

This review highlights the therapeutic potential of epigallocatechin gallate (EGCG) and forskolin in managing retinal diseases, with a focus on glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy. EGCG, a potent polyphenol from green tea, exhibits significant antioxidant, anti-inflammatory, and neuroprotective effects, making it a promising candidate for reducing oxidative stress and inflammation in ocular tissues. Forskolin, a diterpene from Coleus forskohlii, increases cyclic AMP (cAMP) levels, which helps lower intraocular pressure (IOP) and provides neuroprotection. Both compounds target critical pathways involved in retinal disease progression, including oxidative stress, mitochondrial dysfunction, and inflammation, offering complementary therapeutic benefits. This review consolidates preclinical and clinical studies, highlighting the potential of EGCG and forskolin as adjunctive or alternative treatments for retinal diseases. Future research should explore the synergistic effects of these compounds, particularly in combination therapies aimed at addressing multiple pathogenic mechanisms in retinal health. [ABSTRACT FROM AUTHOR]

Background: An unmet need exists when clinically assessing retinal and layer-based features of retinal diseases. Therefore, quantification of retinal-layer-thicknesses/fluid volumes using deep-learning-augmented platforms to reproduce human-obtained clinical measurements is needed. Methods: In this analysis, 210 spectral-domain optical coherence tomography (SD-OCT) scans (30 without pathology, 60 dry age-related macular degeneration [AMD], 60 wet AMD, and 60 diabetic macular edema [total 23,625 B-scans]) were included. A fully automated segmentation platform segmented four retinal layers for compartmental assessment (internal limiting membrane, ellipsoid zone [EZ], retinal pigment epithelium [RPE], and Bruch's membrane). Two certified OCT readers independently completed manual segmentation and B-scan level validation of automated segmentation, with segmentation correction when needed (semi-automated). Certified reader metrics were compared to gold standard metrics using intraclass correlation coefficients (ICCs) to assess overall agreement. Across different diseases, several metrics generated from automated segmentations approached or matched human readers performance. Results: Absolute ICCs for retinal mean thickness measurements showed excellent agreement (range 0.980–0.999) across four cohorts. EZ-RPE thickness values and sub-RPE compartment ICCs demonstrated excellent agreement (ranges of 0.953–0.987 and 0.944–0.997, respectively) for full dataset, dry-AMD, and wet-AMD cohorts. Conclusions: Analyses demonstrated high reliability and consistency of segmentation of outer retinal compartmental features using a completely human/manual approach or a semi-automated approach to segmentation. These results support the critical role that measuring features, such as photoreceptor preservation through EZ integrity, in future clinical trials may optimize clinical care. [ABSTRACT FROM AUTHOR]

Ophthalmic treatment demands precision and consistency in delivering therapeutic agents over extended periods to address many conditions, from common eye disorders to complex diseases. This diversity necessitates a range of delivery strategies, each tailored to specific needs. We delve into various delivery cargos that are pivotal in ophthalmic care. These cargos encompass biodegradable implants that gradually release medication, nonbiodegradable implants for sustained drug delivery, refillable tools allowing flexibility in treatment, hydrogels capable of retaining substances while maintaining ocular comfort, and advanced nanotechnology devices that precisely target eye tissues. Within each cargo category, we explore cutting-edge research-level approaches and FDA-approved methods, providing a thorough overview of the current state of ophthalmic drug delivery. In particular, our focus on nanotechnology reveals the promising potential for gene delivery, cell therapy administration, and the implantation of active devices directly into the retina. These advancements hold the key to more effective, personalized, and minimally- invasive ophthalmic treatments, revolutionizing the field of eye care. [ABSTRACT FROM AUTHOR]

Obesity is a risk factor and pathological basis for various chronic non-communicable diseases and is an important risk factor leading to human mortality and disability. The harm of obesity to the body includes not only various systemic diseases but also some ocular diseases. Currently, the higher pursuit of life and visual quality has led to increased attention to the etiology and prevention of ocular diseases, and the impact of obesity on ocular diseases has been gradually discovered. This article reviews the impact of obesity on certain ocular diseases to deepen the understanding of obesity's impact on ocular diseases and provide a reference for the prevention and treatment of ocular diseases.

Abstract Introduction Neovascular age-related macular degeneration (nAMD) is the leading cause of irreversible vision loss in developed countries. However, a significant gap persists in understanding this population, exacerbated by their advanced age and visual impairments, which can hinder research participation and access to healthcare. The purpose of this study was to describe the content of the questionnaire and the participating patients with nAMD. Methods The survey includes patients diagnosed with nAMD who had previously received treatment or were currently undergoing intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Participants were recruited using various methods, as reaching out to patients who are no longer receiving treatment poses a particular challenge. A patient and public advisory board assisted throughout the study period. Results Of the 713 electronic invitations sent out, 494 (69.3%) patients responded to the questionnaire, with an additional 57 responses obtained through e-mail or telephone interviews. Due to the exclusion of 16 responses, there were a total of 535 valid responses, including 176 from patients previously treated and 359 from those currently undergoing treatment for nAMD. The median age of respondents was 79.9 years (interquartile range [IQR] 75.5–84.7), with 59.8% being women. Among them, 53.2% were married, while 43.1% lived alone. Conclusions Data from the I-OPTA (Identification of Patient-Reported Barriers in Treatment for nAMD) questionnaire allows future exploration of patients who are no longer receiving treatment, patients’ knowledge about preventive measures, and the impact of nAMD on visual function and quality of life. Future research, including studies that integrate data from corresponding retinal images and Danish national registers, has the potential to generate invaluable knowledge, providing benefits to both patients and healthcare professionals.

Owing to the rapid development of modern computer technologies, artificial intelligence (AI) has emerged as an essential instrument for intelligent analysis across a range of fields. AI has been proven to be highly effective in ophthalmology, where it is frequently used for identifying, diagnosing, and typing retinal diseases. An increasing number of researchers have begun to comprehensively map patients' retinal diseases using AI, which has made individualized clinical prediction and treatment possible. These include prognostic improvement, risk prediction, progression assessment, and interventional therapies for retinal diseases. Researchers have used a range of input data methods to increase the accuracy and dependability of the results, including the use of tabular, textual, or image-based input data. They also combined the analyses of multiple types of input data. To give ophthalmologists access to precise, individualized, and high-quality treatment strategies that will further optimize treatment outcomes, this review summarizes the latest findings in AI research related to the prediction and guidance of clinical diagnosis and treatment of retinal diseases.

The retina is composed of neuronal layers that include several types of interneurons and photoreceptor cells, and separate underlying retinal pigment epithelium (RPE), Bruch's membrane, and choroid. Different regions of the human retina include the fovea, macula, and periphery, which have unique physiological functions and anatomical features. These regions are also unique in their protein expression, and corresponding cellular and molecular responses to physiological and pathophysiological stimuli. Skeie and Mahajan analyzed regional protein expression in the human choroid–RPE complex. Mitogen-Activated Protein Kinase (MAPK) signaling pathways have been implicated in responses to stimuli such as oxidative stress and inflammation, which are critical factors in retina diseases including age-related macular degeneration. We, therefore, analyzed the Skeie and Mahajan, 2014, dataset for regional differences in the expression of MAPK-related proteins and discussed the potential implications in retinal diseases presenting with regional signs and symptoms. Regional protein expression data from the Skeie and Mahajan, 2014, study were analyzed for members of signaling networks involving MAPK and MAPK-related proteins, categorized by specific MAPK cascades, such as p38, ERK1/2, and JNK1/2, both upstream or downstream of the respective MAPK and MAPK-related proteins. We were able to identify 207 MAPK and MAPK-related proteins, 187 of which belonging to specific MAPK cascades. A total of 31 of these had been identified in the retina with two proteins, DLG2 and FLG downstream, and the other 29 upstream, of MAPK proteins. Our findings provide evidence for potential molecular substrates of retina region-specific disease manifestation and potential new targets for therapeutics development. [ABSTRACT FROM AUTHOR]

Background: Retinitis pigmentosa (RP) is a group of hereditary retinal dystrophies characterized by progressive degeneration of photoreceptor cells, which results in debilitating visual impairment. This systematic review aims to evaluate the efficacy and safety of emerging treatment modalities for RP, including gene therapy, mesenchymal-cell-based approaches, and supplementary interventions. Methods: A comprehensive search of electronic databases was conducted to identify relevant studies published up to February 2024. Studies reporting outcomes of treatment interventions for RP, including randomized controlled trials, non-randomized studies, and case series, were included. Data extraction and synthesis were performed according to predefined criteria, focusing on assessing the quality of evidence and summarizing key findings. Results: The search yielded 13 studies meeting inclusion criteria, encompassing diverse treatment modalities and study designs. Gene therapy emerged as a promising therapeutic approach, with several studies reporting favorable outcomes regarding visual function preservation and disease stabilization. Mesenchymal-cell-based therapies also demonstrated potential benefits, although evidence remains limited and heterogeneous. Supplementary interventions, including nutritional supplements and neuroprotective agents, exhibited variable efficacy, with conflicting findings across studies. Conclusions: Despite the lack of definitive curative treatments, emerging therapeutic modalities promise to slow disease progression and preserve visual function in individuals with RP. However, substantial gaps in evidence and heterogeneity in study methodologies underscore the need for further research to elucidate optimal treatment strategies, refine patient selection criteria, and enhance long-term outcomes. This systematic review provides a comprehensive synthesis of current evidence and highlights directions for future research to advance the care and management of individuals with RP. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the use of intravitreal anti‐vascular endothelial growth factor (anti‐VEGF) therapy in Norway from 2011 to 2021 and explore how the eye departments organized their injection services. Methods: We combined data from the Norwegian Patient Registry (NPR) with survey responses from Norway's 22 eye departments. The NPR data encompassed all registered intravitreal injection episodes from 2011 to 2021. The survey contained questions about local treatment practices and emphasized neovascular age‐related macular degeneration (nAMD), retinal vein occlusion and diabetic macular edema. Results: A total of 47247 unique patients received 841 646 intravitreal injections in the study period. The number of patients per year increased from 6522 in 2011 to 20 635 in 2021. The number of injections per year increased from 30 926 in 2011 to 125 258 in 2021. The most frequent diagnosis was nAMD. In 2021, the age‐adjusted treatment activity in Norway's 11 counties ranged from 47.8 to 75.5 injections per 1000 inhabitants aged ≥50 years. The use of aflibercept gradually exceeded bevacizumab, but the aflibercept proportion per county ranged from 38 to 82% in 2021. The survey revealed varying treatment practices, local guidelines were often absent, and only half of the departments defined a lower visual limit for initiating or maintaining treatment. Conclusion: The use of intravitreal anti‐VEGF therapy increased considerably from 2011 to 2021, but there was considerable regional variation in treatment activity, drug utilization and organization of injection services. These findings emphasize the need for strengthened governance and national guidelines to ensure equal treatment nationally. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factors (VEGFs) are key mediator of retinal and choroidal neovascularization as well as retinal vascular leakage leading to macular edema. As such, VEGF plays an important role in mediating visually significant complications associated with common retinal disorders such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration. Various drugs that inhibit vascular endothelial growth factors (anti-VEGF therapies) have been developed to minimize vision loss associated with these disorders. These drugs are injected into the vitreous cavity in a clinic setting at regular intervals. This article provides an overview of the various anti-VEGF drugs used in ophthalmology and the common retinal conditions that benefit from this therapy.

This paper introduces a comprehensive dataset of spectral-domain optical coherence tomography (SD-OCT) images of human eyes affected by paracentral acute middle maculopathy (PAMM). Acquired with an SD-OCT device (Optovue, Fremont, California, USA), the dataset includes 133 OCT images of lesions. Each image is paired with a corresponding YOLO label in TXT format, representing manually annotated lesion regions of PAMM, created with the assistance of ophthalmologists. This dataset is invaluable for developing and evaluating automatic algorithms for diagnosing PAMM lesions. By providing detailed annotations and high-quality images, it facilitates advancements in understanding the morphology, progression, and potential treatments of PAMM. Furthermore, it supports the improvement of diagnostic accuracy and the development of targeted therapeutic interventions for retinal diseases. This resource addresses a significant gap in the availability of public datasets focused on PAMM lesions, promoting further research in automated intelligent analysis systems for retinal OCT images.

Diabetic retinopathy is a common yet severe complication of diabetes mellitus and is the leading cause of blindness in middle-aged adults. After years of poorly managed hyperglycemia, complications begin as non-proliferative diabetic retinopathy but can then progress into the proliferative stage marked by neovascularization of the retina. Multiple pathologic mechanisms caused by chronic hyperglycemia damage the retinal vasculature leading to pericyte drop out and the progression of the disease. This review outlines the major pathways of pathogenesis in diabetic retinopathy, highlighting the protective role pericytes play in preserving the blood-retinal barrier. Given the loss of this cell line is a defining feature of the disease, ways in which to prevent pericyte dropout within retinal vasculature is discussed, targeting various pathogenesis pathways of diabetic retinopathy.

BackgroundThe application of Artificial Intelligence (AI) in diagnosing retinal diseases represents a significant advancement in ophthalmological research, with the potential to reshape future practices in the field. This study explores the extensive applications and emerging research frontiers of AI in retinal diseases.ObjectiveThis study aims to uncover the developments and predict future directions of AI research in retinal disease over the past decade.MethodsThis study analyzes AI utilization in retinal disease research through articles, using citation data sourced from the Web of Science (WOS) Core Collection database, covering the period from January 1, 2014, to December 31, 2023. A combination of WOS analyzer, CiteSpace 6.2 R4, and VOSviewer 1.6.19 was used for a bibliometric analysis focusing on citation frequency, collaborations, and keyword trends from an expert perspective.ResultsA total of 2,861 articles across 93 countries or regions were cataloged, with notable growth in article numbers since 2017. China leads with 926 articles, constituting 32% of the total. The United States has the highest h-index at 66, while England has the most significant network centrality at 0.24. Notably, the University of London is the leading institution with 99 articles and shares the highest h-index (25) with University College London. The National University of Singapore stands out for its central role with a score of 0.16. Research primarily spans ophthalmology and computer science, with “network,” “transfer learning,” and “convolutional neural networks” being prominent burst keywords from 2021 to 2023.ConclusionChina leads globally in article counts, while the United States has a significant research impact. The University of London and University College London have made significant contributions to the literature. Diabetic retinopathy is the retinal disease with the highest volume of research. AI applications have focused on developing algorithms for diagnosing retinal diseases and investigating abnormal physiological features of the eye. Future research should pivot toward more advanced diagnostic systems for ophthalmic diseases.

Congenital ocular malformations originate from defective morphogenesis during early eye development and cause 25% of childhood blindness. Formation of the eye is a multi-step, dynamic process; it involves evagination of the optic vesicle, followed by distal and ventral invagination, leading to the formation of a two-layered optic cup with a transient optic fissure. These tissue folding events require extensive changes in cell shape and tissue growth mediated by cytoskeleton mechanics and intercellular adhesion. We hypothesized that the Rho GTPase Cdc42 may be an essential, convergent effector downstream of key regulatory factors required for ocular morphogenesis. CDC42 controls actin remodeling, apicobasal polarity, and junction assembly. Here we identify a novel essential function for Cdc42 during eye morphogenesis in mouse; in Cdc42 mutant eyes expansion of the ventral optic cup is arrested, resulting in microphthalmia and a wide coloboma. Our analyses show that Cdc42 is required for expression of the polarity effector proteins PRKCZ and PARD6, intercellular junction protein tight junction protein 1, β-catenin, actin cytoskeleton F-actin, and contractile protein phospho myosin light chain 2. Expression of RPE fate determinants OTX2 and MITF, and formation of the RPE layer are severely affected in the temporal domain of the proximal optic cup. EdU incorporation is significantly downregulated. In addition, mitotic retinal progenitor cells mislocalize deeper, basal regions, likely contributing to decreased proliferation. We propose that morphogenesis of the ventral optic cup requires Cdc42 function for coordinated optic cup expansion and establishment of subretinal space, tissue tension, and differentiation of the ventral RPE layer.

Abstract The development of treatments targeting the vascular endothelial growth factor (VEGF) signaling pathways have traditionally been firstly investigated in oncology and then advanced into retinal disease indications. Members of the VEGF family of endogenous ligands and their respective receptors play a central role in vasculogenesis and angiogenesis during both development and physiological homeostasis. They can also play a pathogenic role in cancer and retinal diseases. Therapeutic approaches have mostly focused on targeting VEGF-A signaling; however, research has shown that VEGF-C and VEGF-D signaling pathways are also important to the disease pathogenesis of tumors and retinal diseases. This review highlights the important therapeutic advances and the remaining unmet need for improved therapies targeting additional mechanisms beyond VEGF-A. Additionally, it provides an overview of alternative VEGF-C and VEGF-D signaling involvement in both health and disease, highlighting their key contributions in the multifactorial pathophysiology of retinal disease including neovascular age-related macular degeneration (nAMD). Strategies for targeting VEGF-C/-D signaling pathways will also be reviewed, with an emphasis on agents currently being developed for the treatment of nAMD.

Laser photocoagulation is one of the important methods for treating retinal diseases, and retinal laser technology continues to advance. For decades, researchers have been striving to find a laser treatment that can minimize tissue damage while achieving optimal results. With low toxicity, low scattering light, strong penetrating power, small compared with the traditional laser damage, light reaction and no pain, the 577 nm subthreshold micropulse laser(SML)turns this goal into reality and ushers in a new era of laser treatment for fundus diseases. This article reviews the concept, mechanism, related parameters and clinical application progress of 577 nm SML in a variety of retinal diseases, aiming to provide references for clinical treatments.

The development of treatments targeting the vascular endothelial growth factor (VEGF) signaling pathways have traditionally been firstly investigated in oncology and then advanced into retinal disease indications. Members of the VEGF family of endogenous ligands and their respective receptors play a central role in vasculogenesis and angiogenesis during both development and physiological homeostasis. They can also play a pathogenic role in cancer and retinal diseases. Therapeutic approaches have mostly focused on targeting VEGF-A signaling; however, research has shown that VEGF-C and VEGF-D signaling pathways are also important to the disease pathogenesis of tumors and retinal diseases. This review highlights the important therapeutic advances and the remaining unmet need for improved therapies targeting additional mechanisms beyond VEGF-A. Additionally, it provides an overview of alternative VEGF-C and VEGF-D signaling involvement in both health and disease, highlighting their key contributions in the multifactorial pathophysiology of retinal disease including neovascular age-related macular degeneration (nAMD). Strategies for targeting VEGF-C/-D signaling pathways will also be reviewed, with an emphasis on agents currently being developed for the treatment of nAMD. [ABSTRACT FROM AUTHOR]

The rapid advancements in deep learning algorithms and the availability of large, open-access databases of fundus and OCT (optical coherence tomography) images have contributed greatly to advancements in computer-assisted diagnostics and the localization of various disorders affecting the retina. This study offers a comprehensive examination of retinal diseases and various recent applications of deep learning strategies for categorising key retinal conditions, such as diabetic retinopathy, glaucoma, age-related macular degeneration, choroidal neovascularization, retinal detachment, media haze, myopia, and dry eyes. Open-access datasets continue to play a critical role in the advancement of digital health research and innovation within the field of ophthalmology. Thirty open-access databases containing fundus and OCT (optical coherence tomography) pictures, which are often utilised by researchers, were carefully examined in this work. A summary of these datasets was created, which includes the number of images, dataset size, and supplementary items in the dataset, as well as information on eye disease and country of origin. We also discussed challenges and limitations of novel deep learning models. Finally, in conclusion, we discussed some important insights and provided directions for future research opportunities. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is manually predicted by ophthalmologists using features such as variations in length and thickness of blood vessels, lesions like hemorrhages, exudes, and microaneurysms in fundus images. However, the images captured by the fundus camera sensor are prone to noise, undergo uneven illumination, and poor contrast. To effectively identify retinal diseases at an earlier stage, it is necessary to eliminate noise and improve image resolution. A hybrid model for denoising and enhancement is proposed that combines a modified morphological filter and a denoising net. The proposed multi-angle two-stage morphological filter and denoising net (MMFDNet) aids the recovery of a clean image and preserves features from the degraded retinal image. This discriminative learning denoising model removes various noise levels of speckle and additive white Gaussian noise (AWGN) from the fundus image. In Denoising Net, the noisy fundus image is restructured using a down-sampling operation, and the four sub-images are combined with a tunable noise level map, which increases the size of the receptive field by improving the speed and performance of the network. The denoised sub-images are grouped to get the latent image, and the morphological filter is used to improve the quality of the latent image. The effectiveness of this method is tested quantitatively and qualitatively with other existing methods. The databases used to analyze the MMFDNet are proprietary dataset, Messidor and STARE dataset. Compared to existing methodologies, the proposed enhancement technique improves peak signal-to-noise ratio (PSNR) by 2.29%, structural similarity index (SSIM) value by 9.53% and reduces the error by mean square error of 16.31% for Gaussian noise with a noise variance of 0.001. Similarly, improves PSNR by 6.60%, SSIM value by 0.33% and reduces the error by MSE of 47.81% for speckle noise with a noise variance of 0.001. The experimental results illustrate that the proposed MMFDNet outperforms the state-of-the-art methods. [ABSTRACT FROM AUTHOR]

Familial exudative vitreoretinopathy (FEVR) is linked to disruption of the Norrin/Frizzled‐4 signaling pathway, which plays an important role in retinal angiogenesis. Severe or complete knock‐down of proteins in the pathway also causes syndromic forms of the condition. Both heterozygous and biallelic pathogenic variants in the FZD4 gene, encoding the pathway's key protein frizzled‐4, are known to cause FEVR. However, it is not clear what effect different FZD4 variants have, and whether extraocular features should be expected in those with biallelic pathogenic FZD4 variants. Biallelic FZD4 variants were found in a young boy with isolated, severe FEVR. His parents were heterozygous for one variant each and reported normal vision. In‐vitro studies of the two variants, demonstrated that it was the combination of the two which led to severe inhibition of the Norrin/Frizzled‐4 pathway. Our observations demonstrate that biallelic FZD4‐variants are associated with a severe form of FEVR, which does not necessarily include extraocular features. In addition, variants causing severe FEVR in combination, may have no or minimal effect in heterozygous parents as non‐penetrance is also a major feature in dominant FZD4‐FEVR disease. This underscores the importance of genetic testing of individuals and families with FEVR. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is a heterogeneous inherited retinal disorder. Mutations in KIZ cause autosomal recessive (AR) RP. We aimed to characterize the genotype, expression pattern, and phenotype in a large cohort of KIZ cases. Sanger and whole exome sequencing were used to identify the KIZ variants. Medical records were reviewed and analyzed. Thirty-one patients with biallelic KIZ mutations were identified: 28 homozygous for c.226C>T (p.R76*), 2 compound heterozygous for p.R76* and c.3G>A (p.M1?), and one homozygous for c.247C>T (p.R83*). c.226C>T is a founder mutation among patients of Jewish descent. The clinical parameters were less severe in KIZ compared to DHDDS and FAM161A cases. RT-PCR analysis in fibroblast cells revealed the presence of four different transcripts in both WT and mutant samples with a lower percentage of the WT transcript in patients. Sequence analysis identified an exonic sequence enhancer (ESE) that includes the c.226 position which is affected by the mutation. KIZ mutations are an uncommon cause of IRD worldwide but are not rare among Ashkenazi Jews. Our data indicate that p.R76* affect an ESE which in turn results in the pronounced skipping of exon 3. Therefore, RNA-based therapies might show low efficacy since the mutant transcripts are spliced. [ABSTRACT FROM AUTHOR]

Image processing with the help of machine learning algorithms is breaking barriers in various fields of study, especially in the medical field. Deep learning image classification algorithms have made disease detection based on images in an easy manner thus assists the medical professional to taking quick decisions. This paper discusses various deep learning algorithms and transfer learning methods used to classify various eye diseases. Kaggle Eye dataset is used for this purpose. We compared four deep learning algorithms, namely EfficientNetB3, Inception V3, VGG 19 and Convolutional Neural Network models. Various categories of eye diseases, namely Cataract, Diabetic Retinopathy, Glaucoma are considered for classification with normal eye with the help of the scanned images. The strengths and weaknesses of these models are compared based on Precision, Recall, Accuracy and F1 score. In an identical testing environment, EfficientNet B3 outperforms the other algorithms and provides better accuracy for the classification of eye diseases. [ABSTRACT FROM AUTHOR]

The soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) superfamily plays a pivotal role in cellular trafficking by facilitating membrane fusion events. These SNARE proteins, including syntaxins, assemble into complexes that actively facilitate specific membrane fusion events. Syntaxins, as integral components of the SNARE complex, play a crucial role in initiating and regulating these fusion activities. While specific syntaxins have been extensively studied in various cellular processes, including neurotransmitter release, autophagy and endoplasmic reticulum (ER)-to-Golgi protein transport, their roles in the retina remain less explored. This review aims to enhance our understanding of syntaxins' functions in the retina by shedding light on how syntaxins mediate membrane fusion events unique to the retina. Additionally, we seek to establish a connection between syntaxin mutations and retinal diseases. By exploring the intricate interplay of syntaxins in retinal function and health, we aim to contribute to the broader comprehension of cellular trafficking in the context of retinal physiology and pathology. [ABSTRACT FROM AUTHOR]

In eukaryotes such as humans, some non-coding single-stranded RNAs (ncRNAs) help to regulate the pre- and post-transcriptional expression of certain genes, which in turn control many important physiological processes, such as cell proliferation, distinctions, invasion, angiogenesis, and embryonic development. microRNA-126 is an important member of these miRNAs that can be directly or indirectly involved in the control of angiogenesis. Recently, numerous studies have expounded that microRNA-126 can inhibit or promote angiogenesis as well as attenuate inflammatory responses through complex molecular mechanisms. As such, it serves as a biomarker or potential therapeutic target for the prediction, diagnosis, and treatment of relevant diseases. In this review, we present the advancements in research regarding microRNA-126's role in the diagnosis and treatment of related diseases, aiming to provide innovative therapeutic options for the diagnosis and treatment of clinically relevant diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Retinal degenerative disorders (RDDs) cause vision loss by damaging retinal neurons and photoreceptors, affecting individuals of all ages. Cell-based therapy has emerged as an effective approach for the treatment of RDDs with promising results. This meta-analysis aims to comprehensively evaluate the efficacy of cell therapy in treating age-related macular degeneration (AMD), retinitis pigmentosa (RP), and Stargardt macular degeneration (SMD) as the most prevalent RDDs. Methods PubMed, Scopus, Web of Science, and Embase were searched using keywords related to various retinal diseases and cell therapy treatments until November 25th, 2023. The studies’ quality was evaluated using the Joanna Briggs Institute’s (JBI) checklist for quasi-experimental studies. Visual acuity measured as LogMAR score was used as our main outcome. A three-level random-effect meta-analysis was used to explore the visual acuity in patients who received cell-based therapy. Heterogeneity among the included studies was evaluated using subgroup and sensitivity analyses. Moreover, meta-regression for the type of cells, year of publication, and mean age of participants were performed. Results Overall, 8345 studies were retrieved by the search, and 39 met the eligibility criteria, out of which 18 studies with a total of 224 eyes were included in the meta-analysis. There were 12 studies conducted on AMD, 7 on SMD, and 2 on RP. Cell therapy for AMD showed significant improvement in LogMAR (p

Abstract Artificial intelligence (AI) has great potential in ophthalmology. We investigated how ambiguous outputs from an AI diagnostic support system (AI-DSS) affected diagnostic responses from optometrists when assessing cases of suspected retinal disease. Thirty optometrists (15 more experienced, 15 less) assessed 30 clinical cases. For ten, participants saw an optical coherence tomography (OCT) scan, basic clinical information and retinal photography (‘no AI’). For another ten, they were also given AI-generated OCT-based probabilistic diagnoses (‘AI diagnosis’); and for ten, both AI-diagnosis and AI-generated OCT segmentations (‘AI diagnosis + segmentation’) were provided. Cases were matched across the three types of presentation and were selected to include 40% ambiguous and 20% incorrect AI outputs. Optometrist diagnostic agreement with the predefined reference standard was lowest for ‘AI diagnosis + segmentation’ (204/300, 68%) compared to ‘AI diagnosis’ (224/300, 75% p = 0.010), and ‘no Al’ (242/300, 81%, p =

This review highlights the therapeutic potential of epigallocatechin gallate (EGCG) and forskolin in managing retinal diseases, with a focus on glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy. EGCG, a potent polyphenol from green tea, exhibits significant antioxidant, anti-inflammatory, and neuroprotective effects, making it a promising candidate for reducing oxidative stress and inflammation in ocular tissues. Forskolin, a diterpene from Coleus forskohlii, increases cyclic AMP (cAMP) levels, which helps lower intraocular pressure (IOP) and provides neuroprotection. Both compounds target critical pathways involved in retinal disease progression, including oxidative stress, mitochondrial dysfunction, and inflammation, offering complementary therapeutic benefits. This review consolidates preclinical and clinical studies, highlighting the potential of EGCG and forskolin as adjunctive or alternative treatments for retinal diseases. Future research should explore the synergistic effects of these compounds, particularly in combination therapies aimed at addressing multiple pathogenic mechanisms in retinal health.

Despite the recent emergence of multiple cellular and molecular strategies to restore vision in retinal disorders, it remains unclear to what extent central visual circuits can recover when retinal defects are corrected in adulthood. We addressed this question in an Lrat-/- mouse model of Leber congenital amaurosis (LCA) in which retinal light sensitivity and optomotor responses are partially restored by 9-cis-retinyl acetate administration in adulthood. Following treatment, two-photon calcium imaging revealed increases in the number and response amplitude of visually responsive neurons in the primary visual cortex (V1). In particular, retinoid treatment enhanced responses from the ipsilateral eye, restoring the normal balance of eye-specific responses in V1. Additionally, the treatment rescued the modulation of cortical responses by arousal. These findings illustrate the significant plasticity of the adult central visual system and underscore the therapeutic potential of retinoid administration for adults with retinal diseases.

The soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) superfamily plays a pivotal role in cellular trafficking by facilitating membrane fusion events. These SNARE proteins, including syntaxins, assemble into complexes that actively facilitate specific membrane fusion events. Syntaxins, as integral components of the SNARE complex, play a crucial role in initiating and regulating these fusion activities. While specific syntaxins have been extensively studied in various cellular processes, including neurotransmitter release, autophagy and endoplasmic reticulum (ER)-to-Golgi protein transport, their roles in the retina remain less explored. This review aims to enhance our understanding of syntaxins’ functions in the retina by shedding light on how syntaxins mediate membrane fusion events unique to the retina. Additionally, we seek to establish a connection between syntaxin mutations and retinal diseases. By exploring the intricate interplay of syntaxins in retinal function and health, we aim to contribute to the broader comprehension of cellular trafficking in the context of retinal physiology and pathology.

Background Choroideremia is an X-linked inherited retinal degeneration that begins in childhood with nyctalopia and loss of peripheral vision, and gradually progresses to blindness in adulthood. Choroideremia is caused by null mutations in the CHM gene, which encodes Rab escort protein 1. Objective Assessment of the efficacy and safety of a single subretinal injection of an adeno-associated virus serotype 2 vector encoding Rab escort protein 1 in patients with choroideremia. Design Multicentre open-label clinical trial of a gene therapy for choroideremia using an adeno-associated virus serotype 2-Rab escort protein 1 vector. Setting This study (NCT02407678) was conducted at two NHS eye hospitals in the UK. Participants Males aged 18 years or above, having a clinical diagnosis of choroideremia with genetic confirmation of CHM gene mutation or molecular confirmation of Rab escort protein 1 protein deficiency and having best corrected visual acuity better than or equal to 6/60 (20/200; LogMAR 1.0). Intervention Adeno-associated virus serotype 2-Rab escort protein 1 vector suspension (1 × 1012 vector particles per ml) was supplied by Nightstar Therapeutics (London, UK), now part of Biogen Inc. (Cambridge, MA, USA). Up to 0.1 ml of adeno-associated virus serotype 2-Rab escort protein 1 vector suspension, corresponding to a dose of up to 1 × 1011 vector particles, was administered to the treated eye by subretinal injection. Selection of treated eyes was randomised in participants having relatively symmetrical retinal degeneration. Main outcome measures The primary safety-related outcome was change from baseline in best corrected visual acuity in treated eyes at 24 months post treatment, with prospective efficacy evaluated by comparative change from baseline in best corrected visual acuity in treated and untreated contralateral (control) eyes. Secondary outcomes included comparative change from baseline in mean retinal sensitivity (microperimetry) and retinal anatomy (area of autofluorescence) in treated and control eyes. Visual assessments were conducted by masked assessors. Results The primary efficacy-related outcome (comparative change from baseline in best corrected visual acuity in treated and control eyes at 24 months post treatment) was not statistically different between treated eyes (−2.63 letters, standard error of the mean 2.76) and control eyes (+2.67 letters, standard error of the mean 0.768) in all 30 participants (p = 0.08). Greater loss of visual fields, possibly surgery-induced, was observed in treated eyes. Six serious adverse events were reported in the treated eyes of four participants: one surgery-related and two inflammation-related serious adverse events involving clinically significant decreases in best corrected visual acuity, and three serious adverse events in one participant involving reduction in central retinal sensitivity, but with best corrected visual acuity remaining stable. Limitations No evidence of possible efficacy of the intervention was observed, as a meaningful difference in comparative change from baseline in best corrected visual acuity in treated and control eyes was not discernible at 24 months post treatment. As choroideremia is a very slow degeneration, best corrected visual acuity in control eyes did not decline significantly during the assessment period. Conclusion Although this study has not presented evidence that reduction in visual fields caused by the intervention would be justified by the possible rescue of best corrected visual acuity, a more definitive assessment may be provided by long-term monitoring of trial participants in an observational study (NCT03584165). Trial registration This study is registered as ISRCTN15602229 (www.isrctn.com/) and NCT02407678 (https://clinicaltrials.gov/). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/66/35) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 9. See the NIHR Funding and Awards website for further award information. Plain language summary Choroideremia is a rare eye disease caused by a defective gene that prevents the cells in the retina, the light-sensitive layer at the back of the eye, from functioning normally. The disease usually affects males, although females can also develop the disease. In childhood, choroideremia patients initially experience ‘night blindness’, or difficulty in seeing in low light. As the disease progresses, there is a gradual loss in the peripheral vision, eventually resulting in ‘tunnel vision’ and finally in complete blindness by late adulthood. The aim of this study was to investigate if gene therapy was able to prevent further vision loss in patients suffering from choroideremia. The gene therapy for choroideremia uses a modified non-pathogenic virus, called a viral vector, to carry healthy copies of the affected gene into the retinal cells and thereby help the cells to function normally. Thirty male participants from two NHS eye hospitals took part in the study. Each participant received gene therapy in one eye, with the other eye left untreated for purposes of comparison. The condition and function of the treated and untreated (control) eyes were then monitored at regular time points over a 24-month period. A meaningful difference in the comparative rate of vision loss in the treated and control eyes was not observed during the 24-month assessment period of this study. However, it should be noted that choroideremia is a very slow degeneration and vision loss in the control eyes did not decline significantly during this period. Three participants experienced worse vision in their treated eyes, including one case of sight loss caused by severe inflammation that did not respond to medication. Additional data are being collected in a follow-on observational study to track the long-term progress of retinal degeneration in the treated eyes and control eyes of the participants. Scientific summary Background Choroideremia is an X-linked inherited retinal degeneration, affecting approximately 1 in 50,000 people, that begins in childhood with nyctalopia and loss of peripheral vision and gradually progresses to blindness in adulthood. Null mutations in the CHM gene cause a deficiency of Rab escort protein 1 (REP1), leading to degeneration of the retinal pigment epithelium (RPE), followed by secondary degeneration of photoreceptors and the choroid. As the central cone photoreceptors are generally preserved until the late stages of choroideremia, due to the centripetal nature of the degeneration, patients usually retain good visual acuity until degeneration encroaches on the fovea. Gene therapy, a procedure whereby a disease is treated at the genetic level by intracellular delivery of a therapeutic transgene, is an appealing strategy for treating choroideremia. Furthermore, the eye is an attractive site for gene therapy for several reasons. Surgical access is relatively straightforward and gene therapy products can be administered directly to cells in the outer retina (photoreceptors and RPE) by subretinal injection. Potential adverse events can be detected and monitored directly via ocular examination. Therapeutic outcomes can be measured directly using non-invasive assessments of visual function and retinal anatomy, with an untreated contralateral eye available as a control. The risk of systemic immune reactions is reduced by the anatomical compartmentalisation of the eye and the immunological privilege provided by the blood–retina barrier. Moreover, the small tissue volume of the subretinal space means that the therapeutic dose required to treat the retina is several thousand times lower in comparison with doses required for treatment of other organs, further reducing the risk of systemic adverse reactions. Most gene therapies developed thus far as potential treatments for inherited retinal diseases have utilised recombinant adeno-associated virus (AAV) particles as vectors to deliver therapeutic transgenes to target cells in the retina. This gene therapy for choroideremia uses an AAV serotype 2 (AAV2) vector encoding human REP1 protein (AAV2-REP1) that was first tested in human subjects in a phase I/II safety and dose escalation study (NCT01461213) at Oxford (UK). A cohort of six participants was initially treated with a dose of up to 1 × 1010 vector particles administered subretinally in one eye, followed by a cohort of eight participants treated with a higher dose of up to 1 × 1011 vector particles. Two serious adverse events (SAEs) occurred during the clinical trial, comprising a case of retinal thinning due to surgical complications and a case of postoperative inflammation, but otherwise the study data confirmed the safety and possible efficacy of the AAV2-REP1 vector for treatment for choroideremia (Xue K, Jolly JK, Barnard AR, Rudenko A, Salvetti AP, Patrício MI, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med 2018;24:1507–12). An additional 18 choroideremia patients were subsequently treated with a dose of up to 1 × 1011 particles of the same AAV2-REP1 vector administered subretinally in one eye – 6 participants in a phase I/II study (NCT02077361) at Edmonton (Canada), 6 participants in a phase II study (NCT02553135) at Miami (USA) and 6 participants in a phase II study (NCT02671539) at Tübingen (Germany). These studies showed that the AAV2-REP1 vector was generally well tolerated, with a subset of participants achieving clinically significant improvements in best corrected visual acuity (BCVA). One SAE involving a case of postoperative inflammation was reported in the Edmonton study (Dimopoulos IS, Hoang SC, Radziwon A, Binczyk NM, Seabra MC, MacLaren RE, et al. Two-year results after AAV2-mediated gene therapy for choroideremia: the Alberta experience. Am J Ophthalmol 2018;193:130–42). There were no cases of postoperative inflammation reported in the 12 choroideremia patients treated in Tübingen and Miami. In the Tübingen study, a pre-existing degenerative macular hole opened up in one of the participants during surgery but subsequently closed spontaneously (Fischer MD, Ochakovski GA, Beier B, Seitz IP, Vaheb Y, Kortuem C, et al. Efficacy and safety of retinal gene therapy using adeno-associated virus vector for patients with choroideremia: a randomized clinical trial. JAMA Ophthalmol 2019;137:1247–54). In the Miami study, two participants developed an atrophic retinal hole in a non-functioning macular area (Lam BL, Davis JL, Gregori NZ, MacLaren RE, Girach A, Verriotto JD, et al. Choroideremia gene therapy phase 2 clinical trial: 24-month results. Am J Ophthalmol 2019;197:65–73). In view of these satisfactory clinical outcomes, which indicated that gene therapy for choroideremia using the AAV2-REP1 vector demonstrated a good safety profile and sustained gains in BCVA in a proportion of trial participants, the REGENERATE (REP1 gene replacement therapy) phase II study (NCT02407678) was initiated to assess the efficacy of gene therapy (dose of up to 1 × 1011 particles of the AAV2-REP1 vector administered subretinally in one eye) in 30 choroideremia patients at an earlier stage of the disease and therefore still possessing substantial areas of surviving retinal tissue, thereby facilitating the measurement of area changes in order to assess the effect of gene therapy on retinal deterioration. Objectives The aim of the REGENERATE study was to investigate the efficacy and safety of a single subretinal injection of AAV2-REP1 in participants with a confirmed diagnosis of choroideremia over an assessment period of 24 months post treatment. The primary safety-related outcome was change from baseline in BCVA in treated eyes at 24 months post treatment, with prospective efficacy evaluated by comparative change from baseline in BCVA in treated and untreated contralateral (control) eyes. Secondary outcomes included comparative change from baseline in mean retinal sensitivity (microperimetry) and retinal anatomy (area of autofluorescence) in treated and control eyes at 24 months post treatment, as well as change from baseline in safety-related immunological and physiological indicators. Methods Study design The REGENERATE study is an open-label Phase II clinical trial investigating the efficacy and safety of AAV2-REP1 vector-mediated gene therapy for treatment of choroideremia. In contrast to other interventional studies, the REGENERATE study recruited choroideremia patients at an earlier stage of the disease and therefore still possessing substantial areas of surviving retinal tissue. The intention behind this study design was to facilitate the measurement of changes in the area of surviving RPE (determined by fundus autofluorescence) in order to assess the effect of gene therapy on retinal deterioration. Whereas in changes in BCVA and other measures of visual function in the treated eye could be compared against baseline values, assessment of the anatomical rate of degeneration ideally required the untreated contralateral eye to be used as an internal control. This condition required, in turn, the inclusion of participants having a fairly symmetrical disease. In consequence, randomisation of treatment of one eye or the other was also required to avoid selection bias. Sample size As this was an exploratory study to assess a new end point (comparative change from baseline in the area of surviving RPE in the treated and control eyes, determined by fundus autofluorescence), there was no predetermined power calculation to determine the number of trial participants. Instead, data from this trial will be used for future power calculations. A sample size of 30 participants in the REGENERATE study was deemed sufficiently statistically powered to show a signal in the primary end point of efficacy (comparative change from baseline in BCVA in the treated and control eyes) based on power calculations from the original phase I/II study (NCT01461213). Study setting The REGENERATE study was conducted at two NHS eye hospitals, namely, the Oxford Eye Hospital and Moorfields Eye Hospital. These sites were selected based on their expertise and prior experience in conducting clinical trials of retinal gene therapies and their access to specialist clinics for patients with inherited retinal diseases. Participants Participants were males aged 18 years or above, with a clinical phenotype of choroideremia, confirmed genetic or molecular diagnosis and having BCVA better than or equal to 6/60 (20/200; LogMAR 1.0). Candidates were excluded if they had an additional cause for sight loss (e.g. amblyopia) or any other significant ocular and non-ocular disease or disorder which, in the opinion of the investigator, might put them at risk through participation in the study. Allocation for treatment Participants in the REGENERATE study were assigned to one or both of the following cohorts: Cohort 1 included all participants and compared changes in BCVA and other measures of visual function in the treated eye against baseline values. Cohort 2 included the subset of participants with symmetrical disease for whom selection of the treated eye was randomised and compared the rate of anatomical degeneration in the treated eye and the untreated contralateral (control) eye. In the participants with asymmetrical disease (and therefore not included in Cohort 2), the decision about which eye to treat was made on clinical grounds and the worse-affected eye was chosen. Note that randomisation was not used for assigning treatment (vs. placebo/standard care as in randomised controlled trials) to participants included in Cohort 2, but solely for selection of the eye to be treated in these participants for whom the progress of retinal degeneration was relatively symmetrical between the two eyes, defined as a difference in BCVA of no more than one line of letters, as measured on an Early Treatment Diabetic Retinopathy Study chart; and no more than 25% difference in the area of surviving RPE, as measured by fundus autofluorescence. Intervention Adeno-associated virus serotype 2 vector encoding Rab escort protein 1 vector suspension (1 × 1012 vector particles per ml) was supplied by Nightstar Therapeutics (London, UK), now part of Biogen Inc. (Cambridge, MA, USA). Up to 0.1 ml of AAV2-REP1 vector suspension, corresponding to a dose of up to 1 × 1011 vector particles, was administered to the treated eye by subretinal injection. The dose varied slightly dependent on the amount of residual retina. Hence, in more advanced patients, 0.03–0.05 ml might have been sufficient to detach the target area of retina completely. The concentration of vector remained the same. The surgical technique for subretinal administration of the AAV2-REP1 vector suspension has been described previously (MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 2014;383:1129–37). All surgeries took place at the participating hospital sites using the standard BIOM® (binocular indirect ophthalmic microscope) operating system (OCULUS Optikgeräte GmbH, Wetzlar, Germany). The retina was detached with 0.1–0.5 ml of balanced salt solution injected through a subretinal cannula connected to a vitreous injection set. A dose of up to 1 × 1011 vector particles was then injected into the subretinal fluid through the same entry site. Control eyes received no intervention. Assessments Functional assessments included BCVA, contrast sensitivity, dark adaptometry and central visual field mapping (using microperimetry), while anatomical assessments included imaging techniques such as optical coherence tomography and fundus autofluorescence. Safety tests included assessments of ocular and general physical condition, as well as standard blood tests of common physiological markers. Biological samples were also analysed to monitor vector shedding and immunogenicity. Cohort 1 comprised the 30 participants who enrolled in this study, of whom 28 participants had symmetrical disease and were therefore also assigned to Cohort 2. The statistical analyses were therefore performed on the total cohort comparing visual function and anatomical degeneration in treated versus control eyes. Summary statistics of each assessed variable was performed for treated eyes versus control eyes. Data involving a comparison of an assessed variable between the treated and untreated eyes (of each participant) were estimated as the difference between the eyes (with a 95% confidence interval) and simple analysis of change from baseline (paired t-test) was performed at 24 months post treatment. As most participants (93%) had symmetric disease, analysis of covariance was deemed unnecessary. Results Clinical outcomes Overall, BCVA remained relatively stable in treated and control eyes over the 24-month assessment period. A statistically significant deterioration in visual fields was observed in treated eyes compared with control eyes, possibly caused by surgery-induced damage in some treated eyes as manifested by increased loss of autofluorescence and retinal sensitivity at the edges of surviving islands of retinal tissue. The treated eyes underwent retinal detachment prior to injection of the vector suspension into the subretinal space, and this procedure itself can lead to some degree of reduction in central retinal sensitivity and autofluorescence. However, the statistical significance of the comparative reduction in visual fields in treated and control eyes was lost when central retinal sensitivity and area of autofluorescence were analysed in uncomplicated cases. In eyes with no complications, retinal degeneration continued centripetally in both treated and control eyes. Safety Most adverse events were treatable, controlled and resolved without sequelae. Six SAEs were reported in the treated eyes of four participants: one surgery-related and two inflammation-related SAEs involving clinically significant decreases in BCVA and three SAEs in one participant involving reduction in central retinal sensitivity but with BCVA remaining stable. Discussion Main findings of the study There has been no signal of possible efficacy of the intervention (in terms of comparative change from baseline in BCVA between treated and control eyes) over the 24-month assessment period. Overall, BCVA remained relatively stable in treated eyes over the 24-month assessment period. Therefore, in terms of the primary safety-related end point (change from baseline in BCVA in treated eyes at 24 months post treatment), the safety profile of the REGENERATE trial was comparable to other choroideremia gene therapy studies that evaluated the same AAV2-REP1 vector. Limitations of the study No evidence of possible efficacy of the intervention was observed, as a meaningful difference in comparative change from baseline in BCVA in treated and control eyes was not discernible over the 24-month assessment period. As choroideremia is a very slow degeneration, BCVA in control eyes did not decline significantly during the assessment period. Future investigations Future investigations will include a long-term assessment of BCVA, central retinal sensitivity and area of autofluorescence in REGENERATE trial participants in an observational study (SOLSTICE: NCT03584165). Possible approaches to further the investigation of gene therapy for choroideremia include the optimisation of inclusion criteria for subjects still retaining a healthy central retina, which may be more amenable to rescue by gene therapy. Conclusion Although this study has not presented evidence that reduction in visual fields caused by the intervention would be justified by the possible rescue of BCVA, a more definitive assessment may be provided by long-term monitoring of trial participants in an observational study (NCT03584165). Trial registration This study is registered as ISRCTN15602229 (www.isrctn.com/) and NCT02407678 (https://clinicaltrials.gov/). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/66/35) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 9. See the NIHR Funding and Awards website for further award information.

Retinal disease detection and diagnosis relying solely on artificial retinal diseases will put great pressure on doctors and increase the rate of misdiagnosis. Therefore, the development of computer vision technology has brought the possibility for ophthalmologists to use computer-aided diagnosis. In recent years, most models for retinal disease recognition have been based on deep learning, which has the disadvantage of requiring large amounts of data and training time. It is also partly based on broad learning and its disadvantages are that feature extraction ability is limited and poor scalability. To overcome these limitations, we propose a novel artificial intelligence-based approach for the automatic assessment of retinal disease images called a multi-view deep-broad learning network (MDBL-Net), which absorbs the advantages of deep learning and broad learning. MDBL-Net comprises a Multi-view and Multi-scale Feature Extraction (MMFE) module and a Multi-scale Aggregation (MA) block. The MMFE module extracts features of different scales by learning feature representations from multiple views, while the MA block fully aggregates multi-scale deep-broad features from low-level to high-level representations. Experiments were conducted on two public datasets, UCSD and OCT2017. Experiments were conducted on two public datasets, UCSD and OCT2017, and results demonstrate that MDBL-Net achieves high accuracy even with limited training data (only 1%) and significantly reduces training time compared to traditional deep learning models. Specifically, MDBL-Net achieved an accuracy of 96.93% on the UCSD dataset and 99.90% on the OCT2017 dataset, outperforming state-of-the-art models in both cases. These findings suggest that the proposed MDBL-Net approach holds great promise for the task of retinal disease screening and recognition.

Determining indicators or retinal wounds is essential for accurate diagnosis and retinal disorders grading. To view the retinal microarchitecture and easily screen for anomalies, optical coherence tomography (OCT) images are utilized. Numerous studies have already tried to use OCT to overcome that issue. Throughout this study, we describe an OCT image-based transfer learning (TL) approach for the identification of four retinal diseases. This study compares four distinct models with one another. A MobileNetV2 model’s detection accuracy on the test set is 100%; an InceptionNetV3 model’s is 99.9%; an EfficientNet model’s is 99.38%; and a DenseNet model’s is 99.79%. The InceptionNetV3 model approaches the highest accuracy, while MobileNetV2 model achieves the maximum accuracy. The suggested method may influence the development of a tool for automatically identifying retinal disorders. The promising suggested architecture’s qualitative assessments and quantitative outcomes through creating a confusion matrix demonstrate how the suggested methodology can be utilized in healthcare settings as a diagnostic tool to assist medical professionals in making more accurate diagnoses.

Optical coherence tomography (OCT) is an important basis for retinal diagnosis. Traditional OCT image analysis methods not only require a lot of manual operation and time, but also have a certain risk of error. Machine Learning (ML) and Deep Learning (DL) have made significant achievements in the medical field. The Convolutional Neural Networks (CNN) model performs well in extracting local features, but is less effective in extracting global features. The transformer-based structure has an advantage in extracting global features and can make up for this deficiency. This paper proposes a hybrid multi-scale network model based on CNN and Swin transformer, called HRS-Net. The model splits into two branches after the convolutional layers of ResNet50. One branch combines attention modules and residual blocks to extract local features, while the other branch primarily uses Swin transformer blocks to extract global features. Finally, the two branches are fused for the multi-classification task of retinal diseases. Experimental results show that on two public datasets, the accuracy of three-classification and four-classification reached 98.76% and 97.16% respectively, which is better than the previous classic model algorithm.

Background: An unmet need exists when clinically assessing retinal and layer-based features of retinal diseases. Therefore, quantification of retinal-layer-thicknesses/fluid volumes using deep-learning-augmented platforms to reproduce human-obtained clinical measurements is needed. Methods: In this analysis, 210 spectral-domain optical coherence tomography (SD-OCT) scans (30 without pathology, 60 dry age-related macular degeneration [AMD], 60 wet AMD, and 60 diabetic macular edema [total 23,625 B-scans]) were included. A fully automated segmentation platform segmented four retinal layers for compartmental assessment (internal limiting membrane, ellipsoid zone [EZ], retinal pigment epithelium [RPE], and Bruch’s membrane). Two certified OCT readers independently completed manual segmentation and B-scan level validation of automated segmentation, with segmentation correction when needed (semi-automated). Certified reader metrics were compared to gold standard metrics using intraclass correlation coefficients (ICCs) to assess overall agreement. Across different diseases, several metrics generated from automated segmentations approached or matched human readers performance. Results: Absolute ICCs for retinal mean thickness measurements showed excellent agreement (range 0.980–0.999) across four cohorts. EZ-RPE thickness values and sub-RPE compartment ICCs demonstrated excellent agreement (ranges of 0.953–0.987 and 0.944–0.997, respectively) for full dataset, dry-AMD, and wet-AMD cohorts. Conclusions: Analyses demonstrated high reliability and consistency of segmentation of outer retinal compartmental features using a completely human/manual approach or a semi-automated approach to segmentation. These results support the critical role that measuring features, such as photoreceptor preservation through EZ integrity, in future clinical trials may optimize clinical care.

Retinal degeneration (RD) is a significant cause of incurable blindness worldwide. Photoreceptors and retinal pigmented epithelium are irreversibly damaged in advanced RD. Functional replacement of photoreceptors and/or retinal pigmented epithelium cells is a promising approach to restoring vision. This paper reviews the current status and explores future prospects of the transplantation therapy provided by pluripotent stem cell-derived retinal organoids (ROs). This review summarizes the status of rodent RD disease models and discusses RO culture and analytical tools to evaluate RO quality and function. Finally, we review and discuss the studies in which RO-derived cells or sheets were transplanted. In conclusion, methods to derive ROs from pluripotent stem cells have significantly improved and become more efficient in recent years. Meanwhile, more novel technologies are applied to characterize and validate RO quality. However, opportunity remains to optimize tissue differentiation protocols and achieve better RO reproducibility. In order to screen high-quality ROs for downstream applications, approaches such as noninvasive and label-free imaging and electrophysiological functional testing are promising and worth further investigation. Lastly, transplanted RO-derived tissues have allowed improvements in visual function in several RD models, showing promises for clinical applications in the future.