Zhujing Pill ameliorates age-related macular degeneration by regulating lipid metabolism, complement activation, and inflammatory responses: an integrated network pharmacology and metabolomics study.

Reference Standard for Validation of Age-Related Macular Degeneration Screening Algorithms.

Age-related macular degeneration (AMD) is a multifactorial disease that leads to progressive central vision loss. Bevacizumab (Avastin), a therapeutic agent used in the treatment of AMD, exerts its effect by binding to all isoforms of vascular endothelial growth factor (VEGF), thereby inhibiting angiogenesis. This study aimed to investigate the effects of Bevacizumab on immune system cells in the context of neovascular AMD (nAMD) treatment. Patients with nAMD receiving Bevacizumab treatment (n = 18) and a control group of individuals undergoing cataract surgery (n = 19) were included in the study. Peripheral blood samples were collected from nAMD patients before Bevacizumab treatment (baseline, 0 month) and after three monthly intravitreal injections. Following staining with monoclonal antibodies, innate immune cell, T cell, and B cell subsets were analyzed using flow cytometry panels. In the innate immune cell subsets of patients with neovascular AMD (nAMD), immature and suppressive neutrophils were significantly increased, whereas intermediate and non-classical monocytes were significantly decreased. Following intravitreal bevacizumab (IVB) treatment, these cell populations tended to return toward baseline levels. In the adaptive immune compartment, effector memory (EM) T cell subsets, particularly EM1 (effector memory 1) and EM3 (effector memory 3), exhibited opposing dynamics, showing significant changes both before and after IVB treatment. In conclusion, the findings from this study provide preliminary evidence that various immune cell subsets in both innate and adaptive compartments show associations with AMD pathogenesis and with IVB treatment.

Age-related macular degeneration (AMD) is a multifactorial retinal disease in which alterations in lipid metabolism and dysregulation of the complement system play a central role. The aim of this study was to characterize a novel double-knockout (DK) mouse model deficient in apolipoprotein E and complement factor H (ApoE-/-Cfh-/-) as an experimental model of early and intermediate AMD. ApoE-/-Cfh-/- mice and wild-type controls underwent comprehensive morphological, ultrastructural, biochemical, and molecular analyses. Retinal and retinal pigment epithelium (RPE) integrity, Bruch's membrane (BM) morphology, lipid accumulation, complement activation, angiogenic signaling, and synaptic organization were evaluated using histology, electron microscopy, immunohistochemistry, biochemical assays, and gene expression analyses. DK mice exhibited significant RPE thinning, disruption of tight junctions, vacuolization, and BM thickening (p < 0.05). Lipid accumulation and plasma lipid levels significantly increased compared with controls (p < 0.01). Complement activation was significantly enhanced, as evidenced by increased C5b-9 deposition (p < 0.01). In addition, DK mice exhibited increased vascular endothelial growth factor expression (p < 0.05), altered matrix metalloproteinase activity (p < 0.05), and significant synaptic disorganization between photoreceptors and second-order neurons (p < 0.05). The ApoE-/-Cfh-/- mouse reproduces key molecular and structural features of early and intermediate retinal degeneration with statistically significant alterations. Although it does not progress to advanced disease stages, it represents a valuable model to investigate several factors of AMD pathogenesis and evaluate therapeutic strategies targeting early disease mechanisms.

MicroRNAs (miRNAs) play important roles in the pathogenesis of age-related macular degeneration (AMD), while whether polypoidal choroidal vasculopathy (PCV) represents a subtype of AMD remains controversial. However, the differential small non-coding RNA profiles in aqueous humor (AH) between neovascular AMD (nAMD) and PCV remain insufficiently characterized. Therefore, this study aimed to characterize miRNA and piRNA expression profiles in AH samples from nAMD and PCV patients and to explore the potential involvement of these small non-coding RNAs in angiogenesis-related pathways. AH samples were collected from nine cataract controls, eight treatment-naïve nAMD patients, and eight treatment-naïve PCV patients. Small RNA profiles in AH were analyzed using next-generation sequencing (NGS). Differential expression analysis was performed using DESeq2 with adjustment for age, sex, best-corrected visual acuity (BCVA), intraocular pressure (IOP), batch effects, and quality-control covariates. Target gene prediction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were subsequently conducted. Selected miRNAs were partially validated by quantitative PCR (qPCR). To further evaluate their potential relevance to angiogenesis, expression levels of selected miRNAs were additionally examined in a laser-induced choroidal neovascularization (CNV) mouse model. A total of 35 differentially expressed miRNAs were identified between nAMD and PCV, including 28 upregulated and 7 downregulated miRNAs. Moreover, 27 and 47 uniquely expressed miRNAs were detected in nAMD and PCV, respectively. Four miRNAs exhibited opposite expression patterns between the two diseases. Functional enrichment analysis revealed significant involvement of Hippo, MAPK, and neurodegeneration-related signaling pathways. qPCR validation confirmed the differential expression of miR-150-5p and VEGF. In the laser-induced CNV mouse model, miR-150-5p showed expression changes consistent with the human AH sequencing results. Distinct miRNA and piRNA expression profiles were identified between nAMD and PCV, suggesting differential molecular mechanisms underlying the two diseases. These findings improve our understanding of AMD and PCV pathogenesis and may provide potential biomarkers for disease differentiation and angiogenesis-related research.

Macular edema (ME) is a leading cause of visual impairment associated with various retinal pathologies. Spectral-domain optical coherence tomography (SD-OCT) provides high-resolution imaging, allowing detailed assessment of ME patterns and structural changes. The aim of this study was to evaluate the distribution and characteristics of ME across different etiologies using SD-OCT. This cross-sectional observational study included patients with ME from diverse etiologies. SD-OCT was used to assess central macular thickness, retinal volume, cystoid spaces (CS), epiretinal membrane (ERM), hyperreflective foci, and disorganization of retinal inner layers (DRIL). A total of 54% of the study participants were female, with a mean age of 57 years. Diabetes mellitus (50.4%) was the most common etiology, followed by retinal vein occlusions, age-related macular degeneration, ERM, and inflammatory causes. CS were observed in 49.6% of cases, and DRIL in 48%. Severe visual impairment was more frequent in diabetic and vaso-occlusive cases. SD-OCT effectively identifies structural patterns in ME across etiologies, assisting in diagnosis and management planning.

To evaluate the association of hyperreflective foci contiguous with the retinal pigment epithelium (rpeHRF) with visual function impairment in aged normals, early age-related macular degeneration (eAMD), and intermediate AMD (iAMD). Prospective cohort study. Participants of the MACUSTAR study. MACUSTAR participants underwent color fundus photography, optical coherence tomography (OCT) imaging, best corrected visual acuity (BCVA), low-luminance VA (LLVA), rod-mediated dark adaptation (RMDA) at 12°, contrast sensitivity (CS), mesopic (mesPSD), and scotopic pointwise sensitivity deviation (scPSD) testing. rpeHRF presence and count were determined using custom FiJi software. Group comparisons and associations with visual function were analyzed using analysis of variance, linear regression, and Spearman correlation. Presence, burden, and topographic distribution of rpeHRF, as well as association with functional parameters, were determined. Fifty-six normal aged (33 female, mean age 68.1 ± 6.4 years), 34 eAMD (27 female, 71.7 ± 6.4 years), and 583 iAMD eyes (387 female, 72.0 ± 7.0 years) were included. rpeHRF counts were 0.16 ± 0.85 in normals, 0.33 ± 0.96 in eAMD, and 1.61 ± 2.49 in iAMD (P < .001). BCVA, LLVA, CS (all P < .001), and scPSD (P = .001) differed between disease groups, whereas RMDA and mesPSD did not. In iAMD, eyes with rpeHRF showed worse BCVA, LLVA, CS, scPSD (all P < .001), and mesPSD (P = .02). rpeHRF was found to be associated modestly with only CS, scPSD, LLVA, and BCVA. Presence and burden of rpeHRF were independently associated with impaired visual function and may thus serve as a prognostic biomarker for disease progression and enrichment criterion for future interventional trials.

Epiretinal Membrane Is Associated with Acquired Vitelliform Lesion Morphometrics in Intermediate Age-Related Macular Degeneration.

Integrated plasma proteomics and metabolomics reveal immunometabolic pathways and predictive signatures for age-related eye diseases.

Polypoidal choroidal vasculopathy (PCV) is a major subtype of neovascular age-related macular degeneration (nAMD), particularly prevalent in Asian and pigmented populations. While anti-vascular endothelial growth factor (anti-VEGF) therapy has improved outcomes, limitations in durability and incomplete polypoidal lesion regression remain. This review provides an updated synthesis of emerging evidence on newer anti-VEGF agents in PCV management. This narrative review synthesizes recent evidence in PCV management, integrating data from clinical trials and emerging real-world studies, with a focus on newer anti-VEGF agents including faricimab (Vabysmo, Roche/Genentech)and aflibercept 8mg (Eylea HD, Regeneron). Faricimab, a bispecific antibody targeting VEGFA and angiopoietin-2 (Ang-2), demonstrated non-inferior efficacy compared with aflibercept 2mg administered every 8weeks in the TENAYA/LUCERNE trials, with over 70% of patients achieving dosing intervals of ≥ 12weeks. The SALWEEN study further evaluated faricimab in 135 patients with PCV, reporting robust visual gains (+ 8.9 letters), 61% polypoidal lesion regression, and over 80% of patients achieving ≥ 12-week dosing intervals at 48weeks. Aflibercept 8mg, evaluated in the PULSAR trial, demonstrated comparable safety and efficacy with improved anatomical drying and extended dosing intervals (12-16weeks) compared with aflibercept 2mg. In a subgroup analysis of 139 eyes with indocyanine green angiography (ICGA)-confirmed PCV, outcomes were consistent with the overall study population, with similar visual and anatomical improvements but reduced injection burden. More than 80% of eyes achieved dosing intervals of ≥ 12weeks at 2years. Faricimab and aflibercept 8mg represent important advances in PCV management, offering more durable treatment options and reducing treatment burden. However, important gaps remain, including limited real-world data for aflibercept 8mg, absence of head-to-head PCV-specific trials, and uncertainty regarding long-term recurrence and lesion inactivation. These findings support a shift toward increasingly individualized and durable treatment strategies in PCV.

This study aimed to evaluate functional, anatomical, and safety outcomes after switching from aflibercept 2mg to aflibercept 8mg in patients with neovascular age-related macular degeneration (nAMD) requiring short re-treatment intervals in a real-world setting. This single-center prospective observational study included patients with nAMD insufficiently responsive to prior anti-vascular endothelial growth factor (anti-VEGF) therapy requiring re-treatment every 4-6weeks. All eyes had received four consecutive intravitreal injections of aflibercept 2mg prior to switching to aflibercept 8mg as part of routine clinical management. Functional outcome was assessed by distance-corrected visual acuity (DCVA). Anatomical outcomes included central retinal thickness (CRT), central subfield thickness (CST), and optical coherence tomography (OCT) features. Injection burden, responder status, discontinuation, and safety outcomes were evaluated. Follow-up occurred at 3, 6, 9, and 12months. Fifty patients (50 eyes) were included (mean age 78.4 ± 6.9years; 60% female). Median baseline DCVA was 0.19logMAR (IQR 0.12-0.32; 75.5 ETDRS letters), median CST 272µm, and median CRT 338µm. DCVA improved significantly at months3, 6, and 9 (p ≤ 0.046) and remained stable at month12. CRT and CST decreased early and remained improved. Over 12months, 24 patients (48%) completed follow-up, while 26 (52%) discontinued early. Intraocular inflammation (IOI) occurred in 10 eyes (20%), corresponding to 3.0% per injection, and was temporally associated with off-label aliquoted preparation; all cases resolved without permanent visual loss. No further IOI events were observed after transition to on-label preparation. During safety evaluation, seven patients discontinued aflibercept 8mg as a result of precautionary safety measures. Seventeen (34%) required ≤ 8 injections per year. In chronically treated patients with nAMD requiring short re-treatment intervals, switching to aflibercept 8mg was associated with modest anatomical improvement and stable visual function. A reduction in treatment burden was observed in a subset of patients, although overall durability remained heterogeneous and discontinuation rates were high. A cluster of sterile inflammatory events occurred during off-label aliquoted preparation, highlighting the importance of appropriate drug handling. Careful patient selection and strict adherence to on-label preparation procedures are essential to optimize safety. These findings should be interpreted cautiously given the exploratory design, lack of a comparator group, and high discontinuation rate. ClinicalTrials.gov identifier NCT07390253.

Over the past two decades, impressive gains in the restoration and maintenance of visual acuity have been made in patients with, otherwise blinding, chronic retinal diseases such as neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) using intravitreal pharmacotherapy against vascular endothelial growth factor (VEGF). However, there is serious economic burden, continued potential for risks, and potential drug resistance owing to the necessity of repeated injections so as to sustain the initial gains of therapy. Although efforts such as intravitreal treatment with dual pathway inhibitors and sustained drug release implants have been introduced to address such concerns, they do not seem to be the ideal approaches. Consequently researchers continue to explore more plausible solutions, among which tyrosine kinase inhibition seems to have a strong potential to reduce the treatment burden. In this review, the nature of protein kinases and tyrosine kinases, their receptors, and their downstream signaling effects are discussed, followed by the role of receptor tyrosine kinases (RTK) and their inhibitors in the treatment of retinal diseases such as nAMD and DME.

This abstract aimed to explore the potential effect of a higher injection volume with aflibercept 8mg (70μl) versus 2mg (50μl) on intraocular pressure (IOP). In PULSAR (NCT04423718), patients with neovascular age-related macular degeneration (nAMD) were randomised 1:1:1 to receive aflibercept 2mg every 8weeks (2q8) or aflibercept 8mg every 12 (8q12) or 16weeks (8q16), after three initial monthly doses. In PHOTON (NCT04429503), patients with diabetic macular oedema (DME) were randomised 1:2:1 to receive 2q8 after five monthly doses or 8q12 or 8q16 after three initial monthly doses. Increased IOP or glaucoma-related treatment-emergent adverse events (TEAEs) and pre- and post-injection IOP measurements were pooled through week 96 and summarised descriptively. The safety analysis set included 1667 patients (8mg: n = 1164; 2mg: n = 503). Baseline mean (SD) IOP was 15.0 (3.2) mmHg and 15.1 (3.0) mmHg in patients receiving aflibercept 8mg and 2mg, respectively. Rates of TEAEs related to glaucoma (including TEAE of IOP increases) were low and similar across treatment groups (8mg: 9/1000 injections; 2mg: 6/1000 injections). Rates of paracentesis were low (8mg: 1/1000 injections; 2mg: 0). Mean pre-injection IOP values measured at each visit were similar, with no sustained increase over time across treatment groups. Comparable IOP outcomes and no long-term IOP or glaucoma-related effects were observed with aflibercept 8mg versus aflibercept 2mg through week 96. PULSAR (NCT04423718) and PHOTON (NCT04429503) trials.

Neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) can cause substantial vision loss. The 2-mg drug product of aflibercept (AFL-2)-an anti-vascular endothelial growth factor agent-has established efficacy and safety in both diseases. In pivotal trials, a high-dose drug product (AFL-HD) using a formulation distinct from AFL-2 and delivering 8-mg aflibercept every 12 or 16 weeks (following initial monthly dosing) provided visual gains non-inferior to AFL-2 administered every 8 weeks (following initial monthly dosing) and comparable safety with fewer injections over 96 weeks. Free and bound aflibercept concentrations in plasma from 2744 participants in 16 clinical trials where aflibercept was administered intravitreally, subcutaneously, or intravenously were analyzed by population pharmacokinetic modeling. A semi-mechanistic model described the release of free aflibercept from the eye and its target-mediated elimination from plasma. The evaluated covariates (weight, age, sex, albumin, disease, racial classification, Japanese origin, renal and hepatic functions) resulted in only small numerical differences in systemic exposure. Ocular clearance (QE; characterizing the bidirectional transfer of free aflibercept between the eye and central compartment) was comparable across both diseases after adjusting for an age-dependent decrease. The change in drug product, and not just the dose increase, was responsible for a 39.4% slower QE and extended exposure in the ocular space for AFL-HD versus AFL-2. The median ocular concentrations of free aflibercept predicted at the end of the 8-week dosing interval for AFL-2 were typically reached 14 weeks after AFL-HD injections, versus 9-9.5 weeks if QE was identical for both drug products.

Anti-vascular endothelial growth factor (anti-VEGF) therapies are standards of care for vision-threatening retinal diseases. This retrospective observational study describes demographics, utilization, best recorded visual acuity (BRVA), and safety among eyes with neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), diabetic macular edema (DME), or retinal vein occlusion (RVO) treated with the biosimilar aflibercept-ayyh (PAVBLU®) in routine clinical practice. Electronic medical records from the Retina Consultants of America database of patients receiving aflibercept-ayyh (12/1/2024-10/31/2025) were analyzed, focusing on eyes with ≥ 84days of follow-up. The index date was defined as the first documented aflibercept-ayyh injection. Post-index data were used to evaluate treatment patterns, changes in BRVA, and adverse events of special interest (AESIs). Within-eye changes in BRVA were assessed using the Wilcoxon signed rank test and summarized as mean change in logarithm of the minimum angle of resolution (ΔlogMAR). A total of 1000 consecutive eyes from 989 patients (55% female, 43% male, 2% unknown) received 3730 injections of aflibercept-ayyh; 91% switched from prior anti-VEGF therapy and 9% were anti-VEGF treatment-naïve. Disease distribution was 58% nAMD, 19% RVO, 16% DME, and 7% DR. Among switchers, median (IQR) number of prior injections was 21 (8,46). Median (IQR) follow-up was 6.0months (4.6,7.1). Median (IQR) number of aflibercept-ayyh injections per eye was 4 (3,5). Among eyes with ≥ 84days of follow-up (n = 889), mean BRVA logMAR remained stable for switchers (0.4to0.4; P = 0.96) and improved from baseline in anti-VEGF-naïve eyes (0.5to0.4; P < 0.01). Confirmed AESIs included iritis (n = 2; 0.05% of injections), with no events of vitreous cells, endophthalmitis, retinal detachment, retinal vasculitis, or vitreous hemorrhage. In this descriptive real-world analysis, aflibercept-ayyh was associated with stable visual acuity in previously treated eyes and vision improvement in treatment-naïve eyes, with no new or unexpected safety findings, consistent with expectations for aflibercept and the established body of evidence supporting biosimilarity between aflibercept-ayyh and reference aflibercept, EYLEA®).

GBL1204 1.25mg is an ophthalmic-grade bevacizumab formulation, manufactured in accordance with the stringent ophthalmic quality standards, and supplied in a single-use prefilled syringe (PFS). This clinical trial evaluated the short-term safety and biological activity of a single intravitreal injection of ophthalmic bevacizumab in patients with neovascular age-related macular degeneration (nAMD). This phaseI, open-label, single-arm, multicentre trial enrolled 16 participants (aged ≥ 50years) with best-corrected visual acuity (BCVA) score using Early Treatment of Diabetic Retinopathy Study charts of 20/40-20/320 (approximate Snellen equivalent) at five centres across India. Participants were administered a single intravitreal injection of GBL1204 (1.25mg/0.05mL). The main objective was evaluation of ocular and systemic treatment-emergent adverse events (TEAEs), and laboratory parameters over 4weeks. GBL1204 complies with the particulate matter standards specified in the United States Pharmacopeia USP < 789 > for ophthalmic injectable solutions. GBL1204 was safe and well tolerated by the patients over 4weeks. No ocular or systemic serious adverse events occurred. Nine participants (56.25%) reported 14 TEAEs (13 ocular, 1 non-ocular). Of the 14 adverse events, 8 (57.14%) were considered as mild; all adverse events resolved on their own, and without any sequelae. Mean (standard error mean, SEM) BCVA improvement from baseline was + 1.80 (0.76) letters at day7 and + 3.0 (1.10) letters at day28. The corresponding mean (SEM) central macular thickness reductions were - 41.67µm (40.35) and - 64.67µm (42.74) at days7 and 28, respectively. Serum vascular endothelial growth factor levels showed expected suppression consistent with bevacizumab pharmacodynamics. A single intravitreal injection of GBL1204 demonstrated favourable short-term safety and tolerability, with evidence of visual and anatomical improvements. These findings support further evaluation of GBL1204 1.25mg PFS in a pivotal phaseIII trial as a standardized alternative to compounded bevacizumab. Trial Registration Clinical Trial Registry-India (CTRI): Identification no. CTRI/2024/02/063012.

The authors evaluated the alterations of applying artificial intelligence (AI) diagnostic system for diabetic retinopathy screening in real-world practice. This retrospective study included 11,713 diabetic patients from the government-led Diabetes Shared Care Network. The AI system VeriSee DR was integrated into the clinical workflow to identify referable diabetic retinopathy (RDR). Its performance was compared with ophthalmologist grading at the patient level using sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve. Subgroup analysis was performed by age and sex, with additional referral diseases identified by ophthalmologists. VeriSee DR achieved a sensitivity of 0.88, specificity of 0.86, accuracy of 0.86, positive predictive value of 0.58, negative predictive value of 0.97, and area under the receiver operating characteristic curve of 0.87 in detecting RDR. Performance declined with increasing age, whereas sex distribution remained consistent across age groups. The AI system identified a higher proportion of RDR than ophthalmologists (27.45% vs. 18.15%). In addition to 1,818 patients with RDR, ophthalmologists identified other referral-warranted ocular conditions in 4.5% of cases. The AI system referred age-related macular degeneration (Grades 2-4), whereas referral decisions for macular hole and macular edema (Grades 1-2) varied; however, glaucoma (Grades 0-1) identified by clinicians was not consistently referred. VeriSee DR demonstrated high accuracy in detecting RDR but exhibited reduced performance in older patients. It had a higher referral rate than ophthalmologists yet missed certain conditions such as glaucoma. Despite effectiveness in diabetic retinopathy screening, further refinement is required to support broader ophthalmic disease detection.

Enhanced permeation of berberine by ionic liquids for the treatment of posterior age-related macular degeneration following topical delivery

GLP-1 Receptor Agonists and Age-related Macular Degeneration Risk in Diabetes or Non-diabetic Obesity: A Retrospective Cohort Study.

To implement a deep learning-based segmentation algorithm to quantify reticular pseudodrusen (RPD) and drusen volumes on optical coherence tomography (OCT) and investigate their association with progression to late age-related macular degeneration (AMD). A retrospective analysis included study eyes with RPD and contralateral neovascular AMD using 6×6 mm macular OCT (Solix; Visionix/Optovue, Inc). Automated segmentation quantified RPD and drusen volumes, including large drusen and drusenoid pigment epithelial detachment (PED), and late AMD development was evaluated over 2 years. Associations between baseline volumetric biomarkers and progression were evaluated using Cox proportional hazards models. Fifty-one eyes (mean age 74.9±7.65 years) were included. The median (IQR) baseline RPD volume was 0.018 mm³ (0.004-0.52) and total drusen volume was 0.009 mm³ (0.001-0.064). Over 24.2±1.20 months, late AMD developed in 20 eyes (39.2%). In multivariable Cox regression models adjusted for age, each 0.01 mm³ increase in baseline RPD volume (HR: 1.082; p=0.002) and total drusen volume (HR: 1.080; p<0.001) were associated with progression to late AMD. In an exploratory drusen subtype analysis, progression to late AMD was independently associated with baseline RPD volume, large drusen volume and drusenoid PED volume. The deep learning-based volumetric segmentation tool allows OCT-derived automated volume quantification of different types of drusen based on OCT. In eyes with RPD and contralateral neovascular AMD, greater RPD volume and large drusen and/or drusenoid PED volume carried greater risk of developing late AMD in 2 years.