Search Results (1,595)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as cornerstone therapies for type 2 diabetes mellitus and obesity, offering significant cardiovascular and renal protection. However, recent evidence has sparked interest and concern regarding their potential ocular effects. This review critically synthesizes current data on the impact of GLP-1RAs on diabetic retinopathy (DR), nonarteritic anterior ischemic optic neuropathy (NAION), age-related macular degeneration (AMD), and glaucoma or ocular hypertension. While preclinical studies suggest GLP-1RAs exert anti-inflammatory and neuroprotective effects in retinal tissues, clinical data remain mixed. Several large observational studies suggest a protective role against DR and glaucoma, while others raise safety concerns, particularly regarding semaglutide and NAION. Evidence on AMD is conflicting, with signals of both benefit and risk. We also discuss plausible pathophysiological mechanisms and the relevance of metabolic modulation on retinal perfusion. Overall, while GLP-1RAs hold promise for ocular protection in some contexts, vigilance is warranted, especially in patients with pre-existing eye disease. Further ophthalmology-focused prospective trials are essential to clarify long-term safety and guide clinical decision making. Full article

Retinal diseases are among the leading causes of vision impairment worldwide, and early detection is essential for enabling personalized treatments and preventing irreversible vision loss. In this paper, we propose a method aimed to identify and localize retinal conditions, i.e., Age-Related Macular Degeneration, Diabetic Retinopathy, and Choroidal Neovascularization, using explainable deep learning. For this purpose, we consider seven fine-tuned convolutional neural networks: MobileNet, LeNet, StandardCNN, CustomCNN, DenseNet, Inception, and EfficientNet. Moreover, we develop a novel architecture i.e., NeoNet, specifically designed for the detection of retinal diseases, achieving an accuracy of 99.5%. Furthermore, with the aim to provide explaianability behind the model decision, we highlight the most critical regions within retinal images influencing the predictions of the model. The obtained results show the ability of the model to detect pathological features, thereby supporting earlier and more accurate diagnosis of retinal diseases. Full article

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide exerting, among others, strong trophic and protective effects. It plays a role in several physiological functions, including glucose homeostasis. The protective effects of PACAP are mainly mediated via its specific PAC1 receptor by stimulating anti-inflammatory, anti-apoptotic and antioxidant pathways. The aim of the present review is to summarize data on the protective effects of PACAP in the three major complications of diabetes, retinopathy, nephropathy and neuropathy, as well as some other complications. In type 1 and type 2 diabetic retinopathy models and in glucose-exposed cells of the eye, PACAP counteracted the degeneration of retinal layers and inhibited apoptosis and factors leading to abnormal vessel growth. In models of nephropathy, kidney morphology was better retained after PACAP administration, with decreased apoptosis and fibrosis. In diabetic neuropathy, PACAP protected against axonal–myelin lesions and less activation in pain processing centers. This neuropeptide has several other beneficial effects in diabetes-induced complications like altered vascular response, cognitive deficits and atherosclerosis. The promising therapeutic effects of PACAP in several pathological conditions have encouraged researchers to design PACAP-related drugs and to develop ways to enhance tissue delivery. These intentions are expected to result in overcoming the hurdles preventing PACAP from being introduced into therapeutic treatments, including diabetes-related conditions. Full article

Objectives: Retinitis pigmentosa (RP) is commonly initiated by rod photoreceptor degeneration due to genetic mutations, followed by secondary cone loss and progressive blindness. Preserving rod function during the earlier stages of RP is a key therapeutic goal, as rod survival supports cone maintenance and delays vision loss. In this study, we investigated the therapeutic potential of transient knockdown of retinoid-related orphan receptor beta (RORB) using a cell-penetrating asymmetric small interfering RNA (cp-asiRORB) in Rho^P23H mice, a model of autosomal dominant RP. While the role of RORB in the adult retina remains unclear, prior studies of related nuclear receptors suggest potential involvement in proteostasis. Based on this, we hypothesized that persistent RORB expression may influence photoreceptor homeostasis under degenerative stress. Methods: We first optimized the cp-asiRORB design to enhance gene silencing and cellular uptake. In vitro studies were conducted under proteotoxic stress. In vivo studies involved intravitreal administration of cp-asiRORB in Rho^P23H mice. Furthermore, single-cell RNA sequencing of rod photoreceptors was performed. Results: In vitro studies demonstrated that RORB knockdown improved cell viability, reduced apoptosis, and diminished aggresome formation under proteotoxic stress. Intravitreal administration of cp-asiRORB in Rho^P23H mice effectively reduced RORB expression in the retina, leading to improved photoreceptor survival and preserved visual function. Single-cell RNA sequencing revealed upregulation of proteasomal subunit genes in cp-asiRORB-treated eyes, indicating enhanced proteostasis. Conclusions: Together, these results demonstrate that transient suppression of RORB mitigates proteotoxic stress and slows RP progression, highlighting a novel RNAi-based therapeutic strategy for retinal degeneration. Full article

Glaucoma is a chronic, progressive optic neuropathy characterized by the degeneration of retinal ganglion cells. It is one of the leading causes of blindness worldwide, with elevated intraocular pressure (IOP) being the most significant modifiable risk factor. The objective of this paper is to assess the effectiveness of Direct Selective Laser Trabeculoplasty (DSLT) in the management of glaucoma and OHT based on analysis of available literature. Topical hypotensive medications are the preferred first-line therapy for both newly diagnosed open angle glaucoma (OAG) and ocular hypertension (OHT) over other treatment modalities for most patients. Medical glaucoma management, despite proven efficacy, is limited by issues of patient adherence, quality-of-life decrease, side effects, and ocular surface disease (OSD). Selective Laser Trabeculoplasty (SLT) has emerged as a safe, effective, and repeatable alternative to medical therapy for patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). Direct Selective Laser Trabeculoplasty (DSLT) is a novel, non-contact laser treatment that delivers energy transsclerally to the trabecular meshwork (TM) without the use of a gonioscope. In recent studies, DSLT has demonstrated comparable efficacy to conventional SLT, including the multicenter randomized GLAUrious trial. It reduces IOP by 18–27%, often enabling reduction in or discontinuation of hypotensive topical medications. The non-contact, automated nature of DSLT simplifies the procedure, enhances patient comfort, and may expand access to laser therapy across diverse clinical settings. In conclusion, DSLT represents an innovative advancement in laser therapy for glaucoma, combining the clinical benefits of SLT with enhanced procedural efficiency and safety. Further long-term studies are needed to validate its durability, but existing evidence supports its use as a first-line or adjunctive treatment for OAG and OHT. Full article

The relevance of well-structured mitochondria in sustaining the integrity of the retinal pigment epithelium (RPE) is increasingly evident. Conversely, altered mitochondria are a culprit of age-related macular degeneration (AMD), which is influenced by the activity of mechanistic target of rapamycin (mTOR). In the present manuscript, the mitochondrial status of RPE cells was investigated by light and electron microscopy following the administration of various doses of compounds, which modulate mTOR. The study combines MitoTracker dyes and mitochondrial immunohistochemistry with in situ mitochondrial morphometry. Various doses of 3-methyladenine (3-MA), curcumin, and rapamycin were administered alone or in combination. The activity of autophagy and mTOR was quantified following each treatment. Administration of 3-MA led to activation of mTOR, which was associated with severe cell death, altered membrane permeability, and altered ZO-1 expression. In this condition, mitochondrial mass was reduced, despite a dramatic increase in damaged mitochondria being reported. The decrease in healthy mitochondria was concomitant with alterations in key mitochondria-related antigens such as Tomm20, Pink1, and Parkin. Specific mitochondrial alterations were quantified through in situ ultrastructural morphometry. Both curcumin and rapamycin counteract mTOR activation and rescue mitochondrial status, while preventing RPE cell loss and misplacement of decreased ZO-1 expression. Mitigation of mTOR may protect mitochondria in retinal degeneration. Full article

Age-related macular degeneration (AMD) progresses to vision-threatening dry and wet forms, with no effective dry AMD treatments available. The sulfated polysaccharide (GNP, 25.8 kDa) derived from Gelidium crinale exhibits diverse biological activities and represents a potential source of novel therapeutic agents. This study employed a hydrogen peroxide (H₂O₂)-induced oxidative stress and epithelial–mesenchymal transition (EMT) model in retinal pigment epithelial (RPE) cells to investigate GNP’s protective mechanisms against both oxidative damage and EMT. The results demonstrated that GNP effectively suppressed oxidative stress, with the 600 μg/mL dose significantly inhibiting excessive reactive oxygen species (ROS) generation to levels comparable to untreated controls. Concurrently, at concentrations of 200–600 μg/mL, GNP inhibited NF-κB signaling and increased the Bax/Bcl-2 ratio, effectively counteracting H₂O₂-induced oxidative damage and cell apoptosis. Furthermore, in H₂O₂-treated ARPE-19 cells, 600 μg/mL GNP significantly reduced the secretion of N-cadherin (N-cad), Vimentin (Vim), and α-smooth muscle actin (α-SMA), while increasing E-cadherin (E-cad) expression, consequently inhibiting cell migration. Mechanistically, GNP activated the Nrf2/HO-1 pathway, thereby mitigating oxidative stress. These findings suggest that GNP may serve as a potential therapeutic agent for dry AMD. Full article

Inherited retinal dystrophies (IRDs) are clinically and genetically heterogeneous disorders. Most IRDs follow a monogenic inheritance pattern. However, an increasing number of unresolved cases suggest the possible contribution of oligogenic or digenic mechanisms. Here, we report two ultra-rare missense variants—AIPL1 R302L and BBS2 P134R—that co-segregate with early-onset nonsyndromic retinal degeneration in affected individuals from a non-consanguineous family. We performed a multi-level computational investigation to assess whether these variants may act through a convergent pathogenic mechanism. Using AlphaFold2-predicted structures, we modeled both wild-type and mutant proteins, introduced point mutations, and performed energy minimization and validation. FoldX, DynaMut2, and DUET all predicted destabilizing effects at the variant sites, corroborated by local disruption of secondary structure and altered surface electrostatics. Comparative docking (via HDOCK and ClusPro) identified a putative interaction interface between the TPR domain of AIPL1 and the β-sheet face of BBS2. This interface was destabilized in the double-mutant model. At the systems level, transcriptomic profiling confirmed co-expression of AIPL1 and BBS2 in human retina and fetal eye, while functional enrichment analysis highlighted overlapping involvement in ciliary and proteostasis pathways. Network propagation suggested that the two proteins may converge on shared interactors relevant to photoreceptor maintenance. Collectively, these in silico results provide structural and systems-level support for a candidate digenic mechanism involving AIPL1 and BBS2. While experimental validation remains necessary, our study proposes a testable mechanistic hypothesis and underscores the value of computational approaches in uncovering complex genetic contributions to IRDs. Full article

Retinal vasculature is essential for maintaining visual function by supporting metabolically active neurons. However, the retina lacks redundant blood supply, rendering it highly susceptible to vascular dysfunction. Understanding mechanisms of retinal vascular abnormalities is critical for therapies that preserve vascular and neuronal integrity, yet progress has been hindered by limited models and genetic diversity. To address this gap, we examined the retinal vasculature in multiple aged strains from the BXD recombinant inbred mouse panel, a genetically diverse, tractable, and physiologically relevant platform for uncovering novel genetic drivers and disease mechanisms. We identified BXD32 as a striking outlier with dramatically reduced vessel density. Using optical coherence tomography, optical coherence tomography angiography, and histological analyses, we comprehensively characterized retinal vasculature and structural integrity of BXD32 mice during aging. We found progressive, age-dependent vascular dysfunction and degeneration, beginning in the deep capillary plexus and advancing to the intermediate and superficial layers. These changes were accompanied by neuronal degeneration, including photoreceptor loss and thinning of the ganglion cell complex. Our findings establish BXD32 as a spontaneous and genetically tractable model of inherited retinal neurovascular degeneration and provide a foundation for future studies to identify causative genetic loci and underlying molecular mechanisms. Full article

Neovascular age-related macular degeneration (nAMD) is a significant cause of vision loss globally, with intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents forming the cornerstone of treatment. Despite advances, the considerable treatment burden associated with frequent injections and the occurrence of suboptimal responses in some patients highlight an ongoing need for more effective and durable therapeutic options. Faricimab, a bispecific antibody that targets both VEGF-A and angiopoietin-2 (Ang-2), has been developed to address these challenges by promoting greater vascular stability and potentially offering extended treatment intervals. This review synthesizes current evidence from pivotal clinical trials (TENAYA/LUCERNE), real-world studies, meta-analyses, and case reports on the efficacy, durability, and safety of intravitreal faricimab for nAMD. Key efficacy outcomes, such as changes in best-corrected visual acuity and anatomical parameters (e.g., central subfield thickness, retinal fluid dynamics, pigment epithelial detachment morphology), are evaluated in both treatment-naïve and previously treated/treatment-resistant nAMD populations. The safety profile, including intraocular inflammation, retinal vasculitis, retinal pigment epithelium tears, and systemic adverse events, is also comprehensively addressed. Faricimab has demonstrated non-inferior visual outcomes compared to aflibercept 2 mg, alongside robust anatomical improvements and a significant potential for reduced treatment frequency, thereby lessening patient and healthcare system burden. While generally well-tolerated, ongoing monitoring for adverse events remains essential. Full article

Background/Objectives: Glutamatergic neurotransmission is essential for the normal functioning of the retina. Photoreceptor to bipolar and bipolar to ganglion cell signaling is mediated by L-glutamate, which is stored in and released from vesicular glutamate transporter 1 (VGLUT1) containing synaptic vesicles. VGLUT1 is expressed postnatally, P2 onwards, and is required for the glutamatergic retinal wave observed between P10 and P12 in the developing mouse retina. P9–P13 postnatal age is critical for retinal development as VGLUT1 expressing ribbon synapses activate in the outer and inner plexiform layers, and rod/cone mediated visual signaling commences in that period. Although it has been hypothesized that glutamatergic extrinsic signaling drives cell cycle exit and initiates cellular differentiation in the developing retina, it is not clear whether intracellular, synaptic, or extrasynaptic vesicular glutamate release contributes to this process. Recent studies have attempted to decipher VGLUT’s role in retinal development. Here, we investigate the potential effect of genetic loss of VGLUT1 on early postnatal histogenesis and development of retinal neural circuitry. Methods: We employed immunohistochemistry and electrophysiology to ascertain the density of glutamatergic, cholinergic, and dopaminergic cells, spontaneous retinal activity, and light responses in VGLUT1 null retina, and contrasted them with wildtype (WT) and melanopsin null retina. Results: We have demonstrated here that VGLUT1 null retina shows signs of age dependent retinal degeneration, similar to other transgenic mice models with dysfunctional photoreceptor to bipolar cell synapses. The loss of VGLUT1 specifically alters glutamatergic cell density and morphological maturation of retinal ganglion cells. Moreover, VGLUT2 expression is lost in the majority of VGLUT2 cones in the absence of VGLUT1 coexpression, except when VGLUT2 coexpresses transiently with VGLUT3 in these cones, or when VGLUT1 null mice are dark reared. Conclusions: We present the first evidence that synaptic or extrasynaptic postnatal glutamate release from VGLUT1 containing vesicles impacts histogenesis of glutamatergic cells, pruning of retinal ganglion cell dendrites and VGLUT2 expression in cones. Full article

We previously reported ocular phenotypes of 1-year-old 129S1/SvlmJ lysyl oxidase-like 1 null (Loxl1^−/−) mice. Here we sought to characterize age-dependent changes in C57BL/6J Loxl1^−/− mice in a longitudinal fashion. Retinal ganglion cell (RGC) function was assessed by electroretinography (ERG), and optic nerves were evaluated by histological analysis. Ocular biometric measurements were obtained by optical coherence tomography (OCT). We detected reduced RGC function, revealed by decreased amplitude and increased latency of ERG positive scotopic threshold responses (pSTRs) in Loxl1^−/− mice compared to age-matched wt mice. In addition, there is significant inter-eye asymmetry of RGC function, as well as age-related RGC function loss observed only in Loxl1^−/− mice. Histologically, we observed enlarged optic nerve areas in Loxl1^−/− mice compared to wt mice. Significant ocular biometric differences between two groups were detected, most notably, age-related axial elongation of the globe, accompanied by deepening of anterior chamber depth (ACD). Though eyes elongate with age in both groups, this is more pronounced in Loxl1^−/− mice, and the elongation of the globe correlated with decreased RGC function. The correlation of age-related reduction in RGC function with globe axial elongation may have implications for the association of axial myopia with glaucoma and aging in humans. Full article

Background/Objectives: To compare the treatment outcomes of intravitreal faricimab (IVF) and intravitreal aflibercept (IVA) in treatment-naïve patients with neovascular age-related macular degeneration (nAMD), stratified by the presence or absence of punctate hyperfluorescence (PH). Methods: This retrospective study included 301 treatment-naïve patients with nAMD who underwent either IVF or IVA. After 1:1 propensity score matching based on baseline best-corrected visual acuity (BCVA), age, and PH status, 56 eyes (28 per group) were analyzed within each PH subgroup. Outcome measures included BCVA, central retinal thickness (CRT), subfoveal choroidal thickness (SFCT), and no retinal fluid rate during the loading dose regimen, and the retreatment rate after the loading dose regimen. The prespecified primary endpoint was the 1-year retreatment rate after completion of the loading dose regimen, analyzed by Kaplan–Meier curves with log-rank tests. Comparisons were performed separately between the PH and non-PH groups. Results: In the PH group, no significant differences were observed between IVF and IVA groups in terms of BCVA, CRT, SFCT, no retinal fluid rate, or retreatment rate at any time point. In the non-PH group, IVF and IVA groups showed no significant differences in BCVA, CRT, or SFCT at any time point; however, the IVF group achieved a significantly higher no retinal fluid rate (100.0% vs. 64.3%, p < 0.001) and a lower retreatment rate at 1 year (71.4% vs. 92.9%, p = 0.004) than the IVA group. Conclusions: IVF and IVA showed comparable efficacy in nAMD with PH. In contrast, IVF demonstrated superior anatomical outcomes in nAMD without PH. These retrospective findings suggest distinct pathophysiological mechanisms between PH and non-PH subtypes. Full article

Background: Metabolic stress from amino acid (AA) insufficiency is increasingly linked to pathological angiogenesis, but specific essential AA (EAA) roles remain undefined. Neovascular age-related macular degeneration (AMD), a major cause of blindness driven by aberrant ocular neovascularization, has limited efficacy with current VEGFA-targeting therapies. We sought to identify specific EAAs that regulate pathological angiogenesis and dissect their mechanisms to propose new therapeutic strategies. Methods: Human retinal microvascular endothelial cells (HRMVECs) were used to identify angiogenesis-regulating amino acids through systematic EAA screening. The molecular mechanism was investigated using shRNA-mediated knockdown of key stress response regulators (HRI, PKR, PERK, GCN2) and ATF4. Angiogenesis was assessed via tubule formation and migration assays. Therapeutic potential was examined in a laser-induced choroidal neovascularization (CNV) mouse model, evaluated by fluorescein angiography and histomorphometry. Results: Deprivation of methionine, lysine, and threonine potently induced capillary-like tube formation (p < 0.01). Mechanistically, restriction of these three EAAs activated HRI and GCN2 kinases, converging on eIF2α phosphorylation to induce ATF4 and its target VEGFA. Dual, but not single, knockdown of HRI and GCN2 abolished eIF2α-ATF4 signaling and angiogenic responses. Restricting these EAAs exacerbated CNV area in mice. Conclusions: Our findings reveal a coordinated HRI/GCN2-ATF4-VEGFA axis linking EAA scarcity to vascular remodeling, establishing proof-of-concept for targeting this pathway in CNV. This work highlights the therapeutic potential of modulating specific AA availability or targeting the HRI/GCN2-ATF4 axis to treat CNV. Full article

Age-related macular degeneration (AMD) represents a leading cause of irreversible blindness in the elderly, primarily by choroidal neovascularization (CNV) leakage. While intravitreal injections of anti-angiogenic antibodies (e.g., aflibercept) provide clinical benefits, their short half-life necessitates frequent administrations, potentially causing ocular infections or retinal detachment. There is an urgent need for effective antibody delivery systems. Mesoporous silica nanoparticles (MSN) have emerged as promising nanocarriers due to their tunable porosity, surface modifiability, and biocompatibility, though their application in ophthalmology for antibody delivery remains underexplored. We developed two MSN carries: spiky mesoporous silica nanospheres (S-MSN) without amino groups and amine-functionalized hollow dendritic mesoporous silica nanospheres (A-HDMSN). Characterization revealed that A-HDMSN exhibited superior properties, including a larger surface area (550.32 vs. 257.72 m²/g), larger mesoporous pore size (17 vs. <10 nm), and 5.28 times higher drug loading capacity (286.31 ± 8.14 vs. 54.26 ± 3.61 μg/mg) compared to S-MSN (n = 3, p < 0.001), attributable to pore size effects and hydrogen bonding. FITC-labeled A-HDMSN demonstrated efficient uptake by retinal pigment epithelial cells (ARPE-19). Notably, A-HDMSN loaded with Aflibercept (A-HDMSN@Afl) showed significant inhibitory effect on VEGF-induced cell migration even 10 days after drug release in vitro, indicating a favorable sustained-release effect of the drug. These findings highlight A-HDMSN as a promising antibody delivery platform that could extend clinical dosing intervals, offering potential for improved AMD management. Full article