Retinal Diseases Research Articles

Optogenetic therapy for retinal degenerative diseases: A review.

Optogenetics, a cutting-edge tool in novel gene manipulation and drug discovery, holds significant therapeutic potential for a variety of neurological disorders, including retinal diseases. Retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), significantly impair quality of life and cause severe visual impairment due to limited treatment options and a general lack of awareness. The increasing incidence of these degenerative conditions underscores the need for innovative solutions, such as optogenetics. Optogenetic therapy introduces genes coding for light-sensitive proteins, which are controlled by light signals to make neurons photosensitive. This precise targeting approach does not require specific gene intervention and can bypass dysfunctional photoreceptors, offering a treatment option for various degenerative and dystrophic eye diseases. Successful outcomes in patients with late-stage genetic retinal diseases and numerous clinical trials suggest that optogenetics could be an effective treatment for humans. This review provides an overview of the current landscape of optogenetic therapy, discusses its challenges, and summarizes the findings of ongoing clinical trials for neural and visual restoration.

Characterizing Bruch's Membrane: State-of-the-Art Imaging, Computational Segmentation, and Biologic Models in Retinal Disease and Health.

Characterizing Bruch's Membrane: State-of-the-Art Imaging, Computational Segmentation, and Biologic Models in Retinal Disease and Health.

Müller cells trophism and pathology as the next therapeutic targets for retinal diseases.

Müller cells trophism and pathology as the next therapeutic targets for retinal diseases.

Recent Advances in Understanding the Role of PEST Sequence-Containing Proteins in Retinal Neovascularization.

Recent studies have identified significant advancements in understanding the role of PEST sequence-containing proteins in retinal neovascularization. Retinal neovascularization, a critical pathological process, leads to severe visual impairment associated with conditions such as diabetic retinopathy, retinopathy of prematurity, and neovascular age-related macular degeneration. These conditions represent the leading causes of blindness worldwide. Although initially effective, current anti-VEGF treatments can lose efficacy over time and impose a burden due to frequent administrations, highlighting the need for novel therapeutic targets. PEST sequences, characterized by proline, glutamic acid, serine, and threonine enrichment, are structural motifs within proteins that target them for rapid degradation via the ubiquitin-proteasome pathway. Beyond influencing protein degradation, PEST sequences are crucial in regulating angiogenesis and inflammation, essential factors in retinal disease progression. This review focuses on the dual regulatory roles of PEST sequences in VEGFR-2 degradation and stabilization, crucial receptors in angiogenic signaling, as well as their involvement in essential signaling pathways including Notch and JAK/STAT. These findings suggest that PEST sequences could serve as promising new therapeutic targets to control pathological neovascularization and associated inflammatory responses, paving the way for more effective treatments in retinal diseases. Furthermore, advances in gene editing technologies and innovative drug delivery systems enhance the potential for the development of PEST sequence-targeted therapies, offering promising avenues for future clinical applications.

Aqueous humour concentrations of HB-EGF, EGF and VEGF-A and axial length in humans.

To investigate relationships between the intraocular concentrations of heparin-binding epidermal growth factor (HB-EGF), epidermal growth factor (EGF) and vascular endothelial growth factor A (VEGF-A) in dependence on axial length in humans. Clinical interventional cohort study. Patients with cataract who underwent routine cataract surgery. Inclusion criterion was the absence of any retinal or optic nerve disease except for myopic macular degeneration (MMD) without myopic choroidal neovascularization. Using a Luminex system, we measured the concentrations of HB-EGF, EGF and VEGF-A in aqueous humour samples taken from patients during cataract surgery. Intracameral concentration of EGF, HB-EGF and VEGF; Axial length. The study included 68 patients (age: 61.1 ± 11 years; range: 44-85 years) with a mean axial length of 27.11 ± 3.11 mm (range: 22.09-35.64 mm). The HB-EGF concentration (mean: 3.17 ± 0.99 pg/mL) increased with longer axial length (β = 0.43; p < 0.001) and was not associated with age (p = 0.10) and intracameral EGF concentration (p = 0.22). The EGF concentration (mean: 0.22 ± 0.12 pg/mL) increased with longer axial length (β = 0.35; p = 0.004) and higher prevalence of advanced MMD (β = 0.35; p = 0.008) and was not associated with age (p = 0.28) and intracameral VEGF-A concentration (p = 0.09). The VEGF-A concentration (mean: 118 ± 150 pg/mL) decreased with longer axial length (β = -0.54; p < 0.001), higher intracameral concentration of HB-EGF (β = -0.26; p = 0.03) and lower MMD prevalence (β = -0.31; p = 0.02) and was not associated with age (p = 0.47) and intracameral EGF concentration (p = 0.09). With the concentrations of HB-EGF and EGF increasing with longer axial length, the study supports a potential role of the EGFR signalling pathway activation in human axial myopia. The inverse relationship between VEGF-A concentration and longer axial length agrees with a protective effect of axial myopia against diabetic retinopathy and age-related macular degeneration.

Targeted long-read cDNA sequencing reveals novel splice-altering pathogenic variants causing retinal dystrophies.

Splice-altering variants are suggested to be responsible for part of the missing heritability of inherited retinal diseases (IRDs). The interpretation of these variants is challenging as functional evidence is required to validate pathogenicity. We explored the diagnostic value of a targeted long-read cDNA sequencing (lrcDNA-seq) approach to investigate IRD-associated splicing defects. For each affected individual, RNA was isolated from blood and, for each candidate gene, cDNA amplicons, spanning the complete open reading frame or multiple exons, were generated, and subjected to long-read sequencing. We validated our approach by assessing previously described pathogenic splice-altering variants in IRD-associated genes. Next, we investigated six genetically unexplained affected individuals, each carrying pathogenic variant(s) in NMNAT1. In two probands, we provided functional validation for previously identified variants of uncertain significance present on the second allele. In four other subjects, lrcDNA-seq revealed the partial inclusion of an SVA_F retrotransposon in the NMNAT1 mRNA, predicted to introduce a premature stop codon. We showed that targeted lrcDNA-seq is effective in characterizing splice defects and in identifying novel splice-altering variants. We uncovered the IRD genetic basis for six previously unexplained subjects. We believe that the implementation of this technique has the potential to contribute to an increased diagnostic rate of IRDs.

Intravitreal adenine base editing of RS1 improves vision in a preclinical mouse model of retinoschisis.

Intravitreal adenine base editing of RS1 improves vision in a preclinical mouse model of retinoschisis.

High-fat diet alters retinal lipid composition and gene expression networks in mice

BackgroundHigh-fat diet (HFD) was suggested to be associated with several retinal diseases, including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR). Nevertheless, our understanding of the mechanisms governing retinal lipid metabolic homeostasis remains limited, with little attention focused on the influence of HFD on different retinal cell types. To address this gap, we established a high-fat model using mice fed with HFD for a duration of 6 months. Then, we conducted a comparative analysis of the retinal lipidome and proteome between normal diet (ND) and HFD-fed mice to explore the impacts of HFD on retinal lipid metabolism and gene expression network. Furthermore, we also investigated the impacts of HFD on retina in single-cell resolution by single-cell transcriptome sequencing.ResultsWe found that a long-term HFD significantly altered the lipid composition of the retina, with a dramatically elevated cholesterylesters (CE), phosphatidylcholine (PC), and phosphatidylglycerol (PG) level and a decreased eicosanoid level. Proteomic analysis revealed that the primary bile acid biosynthesis pathway was over-activated in HFD retinas. By using single-cell transcriptome analysis, we identified different regulation of gene expression in MG and rod cells in a high-fat environment, whereas the previously identified activation of the bile acid synthesis pathway was predominantly found in MG cells, and may be regulated by alternative pathways of bile acid synthesis, suggesting the critical roles of MG cells in retinal lipid metabolism.ConclusionsTaken together, by multi-omics studies, we unveiled that HFD leading to the development of retinal diseases may be regulated by alternative pathways of bile acid synthesis, and our study will shed light on the treatment of these diseases.

Semaphorin 6A phase separation sustains a histone lactylation–dependent lactate buildup in pathological angiogenesis

Ischemic retinal diseases are major causes of blindness worldwide and are characterized by pathological angiogenesis. Epigenetic alterations in response to metabolic shifts in endothelial cells (ECs) suffice to underlie excessive angiogenesis. Lactate accumulation and its subsequent histone lactylation in ECs contribute to vascular disorders. However, the regulatory mechanism of establishing and sustaining lactylation modification remains elusive. Here, we showed that lactate accumulation induced histone lactylations on H3K9 and H3K18 in neovascular ECs in the proliferative stage of oxygen-induced retinopathy. Joint CUT&Tag and scRNA-seq analyses identified Prmt5 as a target of H3K9la and H3K18la in isolated retinal ECs. EC-specific deletion of Prmt5 since the early stage of revascularization suppressed a positive feedback loop of lactate production and histone lactylation, thus inhibiting neovascular tuft formation. Mechanistically, the C-terminal intrinsically disorder region (IDR) of the transmembrane semaphorin 6A (SEMA6A) forms liquid-liquid phase separation condensates to recruit RHOA and P300, facilitating P300 phosphorylation and histone lactylation cycle. Deletion of endothelial Sema6A reduced H3K9la and H3K18la at the promoter of PRMT5 and diminished its expression. The induction of histone lactylation by SEMA6A-IDR and its pro-angiogenic effect were abrogated by deletion of Prmt5. Our study illustrates a sustainable histone lactylation machinery driven by phase separation-dependent lactyltransferase activation in dysregulated vascularization.

EffiViT: Hybrid CNN-Transformer for Retinal Imaging.

EffiViT: Hybrid CNN-Transformer for Retinal Imaging.

The Protective Effect of Topical PACAP38 in Retinal Morphology and Function of Type 2 Diabetic Retinopathy

The continuously growing diabetes population is a significant concern with type 2 diabetic retinal disease (T2DRD), which is a leading cause of permanent blindness. However, the underlying pathophysiological mechanism of T2DRD has not yet been fully understood. Pituitary adenylate cyclase-activating polypeptide (PACAP) was first isolated from the ovine hypothalamus based on its stimulating effect on the adenylate cyclase enzyme in anterior pituitary cells. PACAP38 (PACAP with 38 amino acids) activates anti-apoptotic pathways, inhibits pro-apoptotic signaling, and creates an anti-inflammatory environment in the retina. The aim of the present study was to test the possible retinoprotective effect of the topical administration of PACAP38 in a type 2 diabetic animal model induced by a high-fat diet and the intraperitoneally injected low-dose streptozotocin (STZ). Wistar rats were divided into four groups: the control, control + PACAP38, diabetes, and diabetes + PACAP38 groups randomly. Type 2 diabetes was induced with the combination of STZ (30 mg/kg) and a high-fat diet. All rats were treated topically two times a day for 16 weeks: the control + PACAP38 and diabetes + PACAP38 groups were applied with PACAP38 eye drops (1 µg/drop), while the control and diabetes groups were administered using vehicles (artificial tears). The diabetes model was validated by a fasting oral glucose tolerance test (OGTT) and C-peptide ELISA test. Animals were monitored during the whole experiment for the progression of the disease using electroretinography (ERG) and optical coherence tomography (OCT). Post-mortem immunohistochemistry and a vessel analysis were performed in the retina samples after 16 weeks. An OGTT, a C-peptide ELISA test, and the investigation of blood parameters proved the development of type 2 diabetes. Significant differences could be detected in visual function between the two diabetic groups at week 16 (in the a-wave, b-wave, and OP amplitudes), where the diabetes PACAP38-treated group was similar to the control ones. OCT measurements correlated with ERG data, where the total retinal thickness was preserved in the diabetes + PACAP38 group. PACAP38 also protected the microvascular structure in the retina. Topically administered PACAP38 has potent neuroprotective effects against type 2 diabetic retinal disease; therefore, it could be a promising therapeutic approach for the treatment of T2DRD.

Retinal Vascular Diseases Highlighted by Adaptive Optics Ophthalmoscopy

Retinal Vascular Diseases Highlighted by Adaptive Optics Ophthalmoscopy

Circadian clock disruption promotes retinal photoreceptor degeneration.

Daily rhythms are a central hallmark of vision, in particular by adapting retinal physiology and light response to the day-night cycle. These cyclic processes are regulated by retinal circadian clocks, molecular machineries regulating gene expression across the 24-h cycle. Although hundreds of genes associated with genetic retinal disorders have been identified, no direct link has been established with the clock. Hence, we investigated the hypothesis that a poorly functioning circadian clock aggravates retinal photoreceptor disease. We performed this study in the P23H rhodopsin-mutated mouse model (P23H Rho) that mimics one major cause of human autosomal dominant retinitis pigmentosa. We also used the rod-specific knockout (rod-Bmal1KO) of Bmal1, a key clock component. More specifically, we used either heterozygous P23H Rho mice or rod-Bmal1KO alone, as well as double mutants of these strains and control mice. We showed by structural (histology, immunohistochemistry) and functional (electroretinography: ERG) analyses that the retinitis pigmentosa phenotype is exacerbated in the double mutant line compared to the P23H Rho mutation alone. Indeed, we observed marked ERG amplitude reduction and more photoreceptor cell loss in double mutants with respect to simple P23H Rho mutants. These observations were further corroborated by transcriptome analysis revealing major gene expression differences between these genotypes. In this data, we identified unique gene expression sets implicating neurogenesis, phototransduction cascade, and metabolism, associated with enhanced photoreceptor degeneration. Thus, our results establish a link between clock dysfunction and retinal degeneration and suggest underlying molecular mechanisms, together providing new concepts for understanding and managing blinding diseases.

Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa.

Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form of IRD, is characterized by gradual dysfunction and degeneration of rod photoreceptors, followed by the loss of cone photoreceptors. Recently, we identified reserpine as a lead molecule for maintaining rod survival in mouse and human retinal organoids as well as in the rd16 mouse, which phenocopy Leber congenital amaurosis caused by mutations in the cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, we show the therapeutic potential of reserpine in a rhodopsin P23H rat model of autosomal dominant RP. At postnatal day (P) 68, when males and females are analyzed together, the reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to the controls with little or no change in scotopic a-wave or cone-derived photopic b-wave. Interestingly, the reserpine-treated female rats display enhanced scotopic a- and b-waves and photopic b-wave responses at P68, along with a better contrast threshold and increased outer nuclear layer thickness. The female rats demonstrate better preservation of both rod and cone photoreceptors following reserpine treatment. Retinal transcriptome analysis reveals sex-specific responses to reserpine, with significant upregulation of phototransduction genes and proteostasis-related pathways, and notably, genes associated with stress response. This study builds upon our previously reported results reaffirming the potential of reserpine for gene-agnostic treatment of IRDs and emphasizes the importance of biological sex in retinal disease research and therapy development.

Myelin regulatory factor (MYRF) is a critical early regulator of retinal pigment epithelial development.

Myelin regulatory factor (Myrf) is a critical transcription factor in early retinal and retinal pigment epithelial development, and human variants in MYRF are a cause for nanophthalmos. Single cell RNA sequencing (scRNAseq) was performed on Myrf conditional knockout mice (Rx > Cre Myrffl/fl) at 3 developmental timepoints. Myrf was expressed specifically in the RPE, and expression was abrogated in Rx > Cre Myrffl/fl eyes. scRNAseq analysis revealed a loss of RPE cells at all timepoints resulting from cell death. GO-term analysis in the RPE revealed downregulation of melanogenesis and anatomic structure morphogenesis pathways, which were supported by electron microscopy and histologic analysis. Novel structural target genes including Ermn and Upk3b, along with macular degeneration and inherited retinal disease genes were identified as downregulated, and a strong upregulation of TGFß/BMP signaling and effectors was observed. Regulon analysis placed Myrf downstream or parallel to Pax6 and Mitf and upstream of Sox10 in RPE differentiation. Together, these results suggest a strong role for MYRF in the RPE maturation by regulating melanogenesis, cell survival, and cell structure, in part acting through suppression of TGFß signaling and activation of Sox10.

Unraveling the effects of serial intravitreal Aflibercept injections on the ocular surface of patients with glaucoma and retinal comorbidity

To evaluate ocular surface and eyelid modifications occurring in glaucomatous patients diagnosed with glaucoma therapy-related ocular surface disease (GT-OSD) and retinal comorbidities who previously underwent serial Intravitreal injections (IVIs) of aflibercept. Thirty-two eyes of 32 patients with a diagnosis of GT-OSD and concomitant retinal diseases were enrolled in a two-center retrospective observational study. The main outcome measures were: Noninvasive tear film break-up time (NIBUT), Tear meniscus height (TMH), Bulbar redness score (BRS), fluorescein Tear film Break Up Time (TBUT), Corneal Fluorescence Staining (CFS), Schirmer test I (ST), and inferior eyelid Meibomian Glands (MGs) dropout. Differences between treated and fellow eye (TE, FE), were considered. The median number of IVIs (aflibercept) in TE was 4 (interquartile range (IQR) 3-6.50). Mean BRS was significantly lower (p = 0.011) and median TBUT higher (p = 0.037) in TE compared to FE. Despite CFS and NIBUT did not significantly differ between eyes, their median values showed a marginal tendency for better results in TE compared to FE. Serial IVIs of aflibercept positively affected some features of the GT-OSD, reducing conjunctival hyperemia and improving the tear film stability. These preliminary results could open to new strategies for ocular surface management in glaucoma, whether confirmed in larger prospective studies.

The Impact of Physical Activity on Retinal Health and Various Retinal Diseases

Introduction: The health benefits of physical activity (PA) are widely known. Currently, its role in maintaining the health of the retina and in treating various diseases of the eye is being intensively studied, which are becoming an increasingly serious public health concern. Purpose of the Work: The aim of this study is to systematize knowledge about the impact of PA on retinal health and to raise awareness of this issue among the public and healthcare professionals. Materials and Methods: This paper is based on a comprehensive review of scientific research conducted worldwide. In the searching process the terms “retina”, “physical activity”, “ocular diseases”, “glaucoma”, “diabetic retinopathy” and “oxidative stress” were used. Results: PA has the potential to counteract microvascular regeneration, promote the body's antioxidant capabilities and enhance anti-inflammatory responses. The protective effect has been observed in both physiological and pathological conditions. Conclusions: PA represents a promising strategy for maintaining retinal health and preventing the progression of various retinal diseases, and may improve the approach to their treatment. Therefore, further research is necessary to establish optimal guidelines regarding the type and intensity of exercise in the context of retinal diseases.

The Metabolic Underpinnings of Retinal Health and Disease: A Focus on Photoreceptor Cells

Review The Metabolic Underpinnings of Retinal Health and Disease: A Focus on Photoreceptor Cells Jianbo Jin 1,2, Qiuping Liu 3,*, and Cheng Li 1,2,4,* 1 Eye Institute &amp; Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen 361102, China 2 Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen 361102, China 3 Department of Ophthalmology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang 421001, China 4 Shen Zhen Research Institute, Xiamen University, Shenzhen 518057, China * Correspondence: liuqiuping1983@gmail.com (Q.L.); cheng-li@xmu.edu.cn (C.L.) Received: 27 October 2024; Revised: 9 December 2024; Accepted: 19 February 2025; Published: 14 April 2025 Abstract: The photoreceptor cells of the retina, encompassing rods and cones, are pivotal in the transduction of light signals into chemical ones, thereby initiating the visual process. This review explores the metabolic bedrock of these cells, which are not only crucial for preserving retinal health but are also susceptible to metabolic stress, precipitating a spectrum of retinal pathologies. The manuscript elucidates the intricate metabolic processes of photoreceptor cells, the synergistic metabolic interplay between photoreceptors and the retinal pigment epithelium (RPE), and appraises the metabolic shifts within photoreceptor cells under conditions of photic injury and diverse pathological states, as well as the ramifications of these metabolic perturbations for retinal function. The review culminates with a prospective horizon scan of research in photoreceptor cell metabolism, charting anticipated investigative trajectories.

Progression, Treatment, and Outcomes of Retinal Vascular Diseases in Pregnancy.

To describe patient characteristics, treatment, and pregnancy outcomes in at-risk patients with retinal vascular diseases occurring during pregnancy. This is a retrospective observational study of pregnant patients seen by a retina specialist, or by any ophthalmologist who coded a retinal vascular disease or precursor as the visit diagnosis, at four tertiary care centers. Outcome measures include prevalence of retinal vascular diseases, progression of diabetic retinopathy (DR), treatment of DR, and adverse pregnancy outcomes. 209 pregnancies from 176 patients met inclusion criteria. Retinal vascular disease was confirmed in 35% (73/209) of pregnancies. Of these, 73% (53) were complicated by DR, 14% (10) by central serous chorioretinopathy, 11% (8) by hypertensive retinopathy, and 5% (4) by retinal vein occlusion. 28% (16/58) of patients with DR required ophthalmologic treatment during pregnancy or postpartum. Rates of preterm birth (54 % vs. 25%, p=0.0004) and C-section delivery (78% vs. 48%, p=0.0004) were significantly higher in patients with a retinal vascular disease. Retinal vascular disease was seen in more than one-third of the at-risk pregnancies in this sample and may represent an important obstetric risk factor, as rates of certain adverse pregnancy outcomes were significantly higher in these patients.

SIGraph: Saliency Image-Graph Network for Retinal Disease Classification in Fundus Image

An efficient and precise diagnosis of retinal diseases is a fundamental goal for auxiliary diagnostic systems in ophthalmology. Inspired by the importance of scattered subtle lesions in manual retinal disease diagnosis, recent research has achieved state-of-the-art performance by mining information related to subtle lesions, including their texture and shape. However, the spatial distribution patterns of subtle lesion areas, which are also crucial in manual diagnosis, have been overlooked in existing research. Neglecting these spatial distribution patterns (e.g., the ring distribution of microaneurysms in diabetic macular edema) may negatively impact the diagnostic process. In this paper, we introduce the Saliency-Image-Graph (SIGraph) network to capture the spatial distribution patterns of lesion areas. We first employ saliency-based perception to identify latent lesion pixels. Subsequently, we propose a novel image-graph block to efficiently capture the global distribution of abundant lesion pixels with minimal information loss. By leveraging additional distribution patterns, SIGraph achieves state-of-the-art performance with at least a 1.5% performance gain across three datasets. Furthermore, ablation studies demonstrate that our image-graph block can be integrated into other visual backbones and effectively boost performance.