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Background Most neovascular age-related macular degeneration treatments involve long-term follow-up of disease activity. Home monitoring would reduce the burden on patients and those they depend on for transport, and release clinic appointments for other patients. The study aimed to evaluate three home-monitoring tests for patients to use to detect active neovascular age-related macular degeneration compared with diagnosing active neovascular age-related macular degeneration by hospital follow-up. Objectives There were five objectives: Estimate the accuracy of three home-monitoring tests to detect active neovascular age-related macular degeneration. Determine the acceptability of home monitoring to patients and carers and adherence to home monitoring. Explore whether inequalities exist in recruitment, participants’ ability to self-test and their adherence to weekly testing during follow-up. Provide pilot data about the accuracy of home monitoring to detect conversion to neovascular age-related macular degeneration in fellow eyes of patients with unilateral neovascular age-related macular degeneration. Describe challenges experienced when implementing home-monitoring tests. Design Diagnostic test accuracy cohort study, stratified by time since starting treatment. Setting Six United Kingdom Hospital Eye Service macular clinics (Belfast, Liverpool, Moorfields, James Paget, Southampton, Gloucester). Participants Patients with at least one study eye being monitored by hospital follow-up. Reference standard Detection of active neovascular age-related macular degeneration by an ophthalmologist at hospital follow-up. Index tests KeepSight Journal: paper-based near-vision tests presented as word puzzles. MyVisionTrack®: electronic test, viewed on a tablet device. MultiBit: electronic test, viewed on a tablet device. Participants provided test scores weekly. Raw scores between hospital follow-ups were summarised as averages. Results Two hundred and ninety-seven patients (mean age 74.9 years) took part. At least one hospital follow-up was available for 317 study eyes, including 9 second eyes that became eligible during follow-up, in 261 participants (1549 complete visits). Median testing frequency was three times/month. Estimated areas under receiver operating curves were < 0.6 for all index tests, and only KeepSight Journal summary score was significantly associated with the lesion activity (odds ratio = 3.48, 95% confidence interval 1.09 to 11.13, p = 0.036). Older age and worse deprivation for home address were associated with lower participation (χ2 = 50.5 and 24.3, respectively, p 6 and < 42 months earlier. We tried to recruit equal numbers by time since starting treatment in the first-treated study eye (6–17 months; 18–29 months; 30–41 months) to ensure test performance was estimated across this range of duration of nAMD. Patients were followed for at least 6 months. Reference standard The reference standard was the reviewing ophthalmologist’s decision about the activity status of a study eye at a HES monitoring visit, recorded as active, inactive or uncertain. There were no additional hospital visits for the study. Such decisions are usually based on clinical examination and the results of hospital-based retinal imaging investigations, for example, colour fundus photographs and ocular coherence tomograms (OCTs). The reference standard grouped uncertain with inactive judgements for analyses. Index tests Three home-monitoring (‘index’) tests were evaluated, spanning low to moderate cost and complexity. These were: KeepSight Journal (KSJ): a paper-based booklet of near-vision tests presented as word puzzles developed in the United States and adapted by the study team for use in the study. MyVisionTrack® (mVT®): electronic vision test, intended to be viewed on a tablet device. MultiBit (MBT): electronic vision test, intended to be viewed on a tablet device. Specific thresholds indicating a significant clinical change were not provided for any of index tests in advance by their developers. Outcomes The primary outcome was classification of a study eye at a monitoring visit as having active or inactive disease (active, inactive, uncertain), that is, the reviewing ophthalmologist’s decision. A secondary outcome (new reference standard) for Objective A was a change from inactive to active status from one management visit to the next. This was considered better to represent how home monitoring might be implemented. For Objective C, outcomes investigated were willingness in principle to participate; ability to carry out index tests; adherence to weekly testing. For Objective D, the outcome was conversion of a fellow eye to active nAMD as judged by an ophthalmologist, that is, same reference standard. For Objective E, the following outcomes were described as measures of the technical and logistical challenges identified during the study: Frequency and reason for incoming calls made to the helpline and outgoing calls made to participants. Frequency and duration of events leading to the digital tests being unavailable for testing. Other technical and logistical challenges. Objective B study recruitment and data collection Recruitment to the qualitative component began 3 months after the monitoring for neovascular age-related macular degeneration reactivation at home (MONARCH) study began recruiting. During the consent process for participation in the study, patients could consent to further contact from the qualitative research team to discuss participation in the qualitative study. Maximum variation sampling ensured a range of perspectives were captured in relation to: age (young-old 50–69 years and older-old > 70 years), gender, one or both eyes with nAMD, time since first treatment (defined as above) and adherence to home monitoring (test data from the two electronic tests were used to categorise participants into ‘regular’ testers and ‘irregular’ testers). Patients who declined to participate in MONARCH but provided consent to be contacted about the qualitative study, informal ‘carers’, supporters or significant others in the lives of patients and healthcare professionals who interacted with participants at study sites visits were also approached to gather their perspectives about the acceptability of home monitoring. Statistical analysis Objective A: The test accuracy of index tests was estimated by fitting a logistic regression model to predict the reference standard from summary test scores for the interval between monitoring visits, adjusting for participants’ baseline data. Accuracy was estimated for the primary outcome using all index test data, data only for the 4 weeks preceding the monitoring visit, the reference standard based on reading centre decisions made from OCT images and for the secondary outcome. Test scores were summarised as: means (MBT and mVT); median (KSJ reported near visual acuity (VA), ordinal six-point scale); proportions (KSJ reported VA, Amsler grid and household object appearance reported worse than baseline vs. same or better). All four scores were fitted in the KSJ model and a single area under the receiving operator curve (AUROC) was estimated. Separate models were fitted for each test for the primary outcome, the two sensitivity analyses and the secondary outcome. Model performance was quantified by the odds ratio (OR) for the index test summary score(s) and the estimate of the AUROC and their respective confidence intervals (CIs). AUROCs were based on predicted probabilities calculated using only the fixed effects in the models. Sensitivity, specificity, positive and negative predictive values and 95% CIs were calculated using cut-off thresholds corresponding to Youden’s index for each model, which minimises overall misclassifications. Average test scores above and below the thresholds were also calculated. Analyses took account of the structure within the data, that is, the nesting of visits and eyes within patients. Objective B: All interviews were audio-recorded and transcribed. A directed content analysis approach based on deductive and inductive coding was used. NVivo version 12 was used to manage data and facilitate the analysis process, which, in summary, included the following stages: (1) independent transcription, (2) data familiarisation, (3) independent coding, (4) development of an analytical framework, (5) indexing, (6) charting and (7) interpreting data. Objective C: Willingness in principle to participate was defined as an approached eligible patient agreeing to attend a research visit for training. Ability to perform an index test was defined as the proportion of monitoring visits for which some valid index test data were available. Adherence was defined as the proportion of weeks between monitoring visits for which some valid data for an index test were available. The ability and adherence models were performed for each test separately at the level of the patient. Regression models estimated associations of age, sex, Index of Multiple Deprivation (IMD), stratum of time since first diagnosis and baseline visual acuity at diagnosis on the outcomes of willingness to participate, ability to perform tests and adherence to weekly testing; models for the latter two outcomes were fitted for each index test. Associations were reported with 95% CIs. Analyses of adherence and ability took account of nesting of visits within participants. Objective D: The test accuracy of the index tests for the reference standard of an ophthalmologist’s classification of a fellow eye as having active disease at a monitoring visit, that is, conversion to active nAMD, was estimated by the same methods as described for Objective A. Two sensitivity analyses were carried out: (1) the same reference standard but using test data only for the 4 weeks preceding the management visit and (2) the alternative reference standard of classification of a fellow eye having active disease based on reading centre grading of OCTs carried out during the monitoring visits. Objective E: This objective used descriptive summary descriptive statistics only. Results The study recruited 297 patients (consented participants) between 21 August 2018 and 31 March 2020. Half of recruited participants were first treated for nAMD 6–17 months before consenting, 28% 18–29 months before consenting and 22% 30–41 months before consenting. At the end of the study, data for at least one monitoring visit after starting to use the index monitoring tests were available for 357 study eyes in 297 patients. Data were available for at least one complete monitoring visit after starting to use the index monitoring tests for 317 study eyes of 261 patients. More participants were women (58.6%). Participants’ mean age was 74.9 (6.6) years [standard deviation (SD)]. The mean visual acuity of study eyes (better seeing eyes if participants had two study eyes) was 0.2 (0.2) Logarithm of the minimum angle of resolution (LogMAR) (SD). Objective A: Median testing frequency was three times per month. In the primary analysis, estimated AUROCs were < 0.6 for all index tests, and only KSJ summary score was significantly associated with the lesion activity (OR = 3.48, 95% CI 1.09 to 11.13; p = 0.036). Estimated AUROCs were < 0.6 for all tests in both sensitivity analyses and for the secondary outcome of change from inactive to active status between adjacent management visits. Objective B: Two overarching meta-themes emerged from the qualitative studies related to acceptance or non-acceptance of home monitoring. Meta-theme 1 encompassed four main themes: (1) the role of home monitoring; (2) suitability of procedures and instruments; (3) experience of home monitoring; and (4) feasibility of home monitoring in usual practice. Meta-theme 2 consisted of one main theme covering key inhibitors to acceptability. The main factors influencing acceptability included a participant’s understanding about the purpose of home monitoring and their experience of using it. While home monitoring was generally seen as a relatively straightforward exercise to undertake and non-burdensome, training and ongoing support were regarded as essential to its success. Home monitoring was acceptable to patients and its potential to reduce clinic visits during non-active treatment phases was recognised. Objective C: A minority of patients who were approached were willing in principle to participate. Increasing age and worse deprivation index for home address were associated with being unwilling in principle to participate (χ2 = 50.5 and 24.3, respectively, both p ≤ 0.001). Recruiting site was also associated with willingness in principle to participate, believed to be due to sites adopting different strategies for approaching and recruiting patients. Increasing age and worse deprivation were not consistently associated with either being able to self-monitor with the index tests or adherence to weekly testing (χ2 for all tests 0.08 for ability and adherence, except for worse IMD being associated with better adherence for the KSJ, χ2 = 12.15, p = 0.016). Recruiting site was also associated with being able to test and adhering to weekly testing. Objective D: There were 132 fellow eyes with data from 544 monitoring visits, 17 of which (12.9%) had nAMD recorded at one or more management visits over about 100 participant-years. This rate of conversion was higher than expected based on epidemiological studies of conversion rates in unaffected fellow eyes, potentially due to study eyes having had nAMD longer ago. Some predictors could not be fitted in models and estimates of associations were imprecise. The no-test model predicted conversion better than for Objective A (AUROC = 0.73) and electronic tests did not increase this (AUROCs = 0.73 and 0.76 for MBT and mVT, respectively). The estimated AUROC for the KSJ was 0.85, due to a strong positive association of the household object summary score with conversion (OR 15.3, p = 0.036). Objective E: Despite two-thirds of the population having previously used a smartphone, there were still a variety of challenges experienced with the electronic devices while testing at home that contributed to both reduced adherence and ultimately withdrawals from the study. Strengths and limitations The study had several strengths. Estimates of the diagnostic test accuracy of index tests were at low risk of bias: the study population was appropriate for the intended use of the tests, and summary test scores were not available to ophthalmologists providing the reference standard, which was judged after the index test data were collected. Limitations A smaller-than-planned sample size (less than half the target number of monitoring visits); nonetheless, 95% CIs for AUROCs were narrow (± 0.04) and estimates were able to rule out tests providing adequate accuracy for diagnosing active nAMD to enable patients to be monitored without hospital review. Tests were sometimes not available for technical reasons that were beyond the control of the research team. The study had no control over monitoring visits and participants are likely to have reported their subjective visual experience to their consultants, which might have influenced the reference standard. We could not define test thresholds a priori, and instead estimated AUROCs. We did not compare AUROCs for tests due to their poor accuracy. The ways in which patients were approached and screened varied across sites, generating a site effect in analyses of potential inequalities; variations may have reflected the pre-conceptions of research staff regarding the capabilities of patients to use the electronic tests. Conclusions Based on the detection of lesion activity assessed by clinicians in the clinic, we have shown that none of the index tests provides acceptable test accuracy for home monitoring in this context. Associations of increasing age and deprivation index for home address with unwillingness in principle to participate despite provision of hardware highlight the potential for inequality with interventions of the kind evaluated. While a proportion of nAMD patients are willing and interested in the potential for home monitoring, substantial practical and technological issues are encountered in the implementation of such, requiring a significant support infrastructure, including a study helpline. Future work Future research should focus on the methodological challenge of efficiently evaluating mobile health technologies which deal with constantly emerging new technology. The clear evidence of inequalities in participation and retention should prompt future research on ways to encourage participant and adoption of mobile health technologies by underserved populations. Focus should also be placed on methods to improve adherence and retention in longitudinal studies involving electronic testing, particularly around the nature of feedback to participants. Trial registration This trial is registered as ISRCTN79058224. Funding This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/97/02) and is published in full in Health Technology Assessment; Vol. 28, No. 32. See the NIHR Funding and Awards website for further award information.

Age-related macular degeneration (AMD), characterized by macular retinal degeneration, poses a significant health concern due to the lack of effective treatments for prevalent dry AMD. The progression of AMD is closely linked to reactive oxygen species and Fas signaling, emphasizing the need for targeted interventions. In this study, we utilized a NaIO3-induced retinal degeneration mouse model to assess the efficacy of Fas-blocking peptide (FBP). Intravitreal administration of FBP successfully suppressed Fas-mediated inflammation and apoptosis, effectively arresting AMD progression in mice. We developed a 6R-conjugated FBP (6R-FBP) for eye drop administration. 6R-FBP, administered as an eye drop, reached the retinal region, attenuating degeneration by modulating the expression of inflammatory cytokines and blocking Fas-mediated apoptosis in rodent and rabbit NaIO3-induced retinal degeneration models to address practical concerns. Intravitreal FBP and 6R-FBP eye drops effectively reduced retinal degeneration and improved retinal thickness in rodent and rabbit models. This study highlights the therapeutic potential of FBP, particularly 6R-FBP as an eye drop, in inhibiting Fas-mediated cell signaling and protecting against retinal cell death and inflammation in dry AMD. Future investigations should explore the translational prospects of this approach in primates with eye structures comparable to those of humans. [ABSTRACT FROM AUTHOR]

Wet age‐related macular degeneration (AMD) is a common cause of vision loss in the elderly. It is characterised by choroidal neovascularisation (CNV), caused by overexpression of vascular endothelial growth factor (VEGF), resulting in abnormal vessel proliferation. Current clinical management predominantly relies on anti‐VEGF agents, which require frequent and costly injections. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has emerged as a promising strategy for permanently suppressing angiogenesis by targeting the VEGF‐related pathway. Increased research suggests that disrupting this pathway holds potential for preventing CNV progression. This review provides an overview of the aetiology, classification and pathophysiology of wet AMD, followed by a concise summary of current gene editing research using the CRISPR/Cas system via viral vector delivery strategies to target ocular pro‐angiogenic factors, including Hif‐1α, VEGF and VEGFR. The importance of timely targeting of VEGFA is emphasised and the challenges associated with gene editing therapies are also highlighted. [ABSTRACT FROM AUTHOR]

Exploratory data analysis and statistical moments were used to investigate the potential impact of ceiling and floor effects in medical trials. A total of 150 treatment-naive eyes were assessed in a retrospective case study of patients who were treated with anti-VEGF injections for wet age-related macular degeneration. The experimental results revealed that ceiling and floor effects are problematic in data analysis and may result in serious errors when using standard parametric tests. The case study provided insights relating to methodology in medical trials, experimental data analysis, and statistical inference, as applied to the interpretation of treatment response limits. Suggestions are provided for statistical data pre-processing and post-processing when significantly skewed distributions are present in response groups.

Exploratory data analysis and statistical moments were used to investigate the potential impact of ceiling and floor effects in medical trials. A total of 150 treatment-naive eyes were assessed in a retrospective case study of patients who were treated with anti-VEGF injections for wet age-related macular degeneration. The experimental results revealed that ceiling and floor effects are problematic in data analysis and may result in serious errors when using standard parametric tests. The case study provided insights relating to methodology in medical trials, experimental data analysis, and statistical inference, as applied to the interpretation of treatment response limits. Suggestions are provided for statistical data pre-processing and post-processing when significantly skewed distributions are present in response groups. [ABSTRACT FROM AUTHOR]

Wet age‐related macular degeneration (wet AMD) is the most common cause of blindness, and chronic intravitreal injection of anti‐vascular endothelial growth factor (VEGF) proteins has been the dominant therapeutic approach. Less intravitreal injection and a prolonged inter‐injection interval are the main drivers behind new wet AMD drug innovations. By rationally engineering the surface residues of a model anti‐VEGF nanobody, we obtained a series of anti‐VEGF nanobodies with identical protein structures and VEGF binding affinities, while drastically different crystallization propensities and crystal lattice structures. Among these nanobody crystals, the P212121 lattice appeared to be denser and released protein slower than the P1 lattice, while nanobody crystals embedding zinc coordination further slowed the protein release rate. The polymorphic protein crystals could be a potentially breakthrough strategy for chronic intravitreal administration of anti‐VEGF proteins. [ABSTRACT FROM AUTHOR]

In recent years, there has been a captivating focus of interest in elucidating the intricate crosstalk between adiponectin (APN), a versatile fat-associated adipokine and ocular pathologies. Unveiling the intricate relationship between adipocytokine APN and its receptors (AdipoRs) with aging eye disorders has emerged as a fascinating frontier in medical research. This review article delves into this connection, illuminating the hidden influence of APN on retinal health. This comprehensive review critically examines the latest findings and breakthroughs that underscore the pivotal roles of APN/AdipoRs signaling in maintaining ocular homeostasis and protecting against eye ailments. Here, we meticulously explore the intriguing mechanisms by which APN protein influences retinal function and overall visual acuity. Drawing from an extensive array of cutting-edge studies, the article highlights APN's multifaceted functions, ranging from anti-inflammatory properties and oxidative stress reduction to angiogenic regulation within retinal and macula tissues. The involvement of APN/AdipoRs in mediating these effects opens up novel avenues for potential therapeutic interventions targeting prevalent aging eye conditions. Moreover, this review unravels the interplay between APN signaling pathways and age-related macular degeneration (AMD). The single-cell RNA-seq results validate the expression of both the receptor isoforms (AdipoR1/R2) in retinal cells. The transcriptomic analysis showed lower expression of AdipoR1/2 in dry AMD pathogenesis compared to healthy subjects. The inhibitory adiponectin peptide (APN1) demonstrated over 75% suppression of CNV, whereas the control peptide did not exert any inhibitory effect on choroidal neovascularization (CNV). The elucidation of these relationships fosters a deeper understanding of adipose tissue's profound influence on ocular health, presenting new prospects for personalized treatments and preventative measures. Because APN1 inhibits CNV and leakage, it can be used to treat human AMD, although the possibility to treat human AMD is in the early stage and more clinical research is needed. In conclusion, this review provides a captivating journey into the enthralling world of APN, intertwining the realms of adipose biology and ophthalmology in aging. [ABSTRACT FROM AUTHOR]

Abstract Wet age‐related macular degeneration (AMD) is a common cause of vision loss in the elderly. It is characterised by choroidal neovascularisation (CNV), caused by overexpression of vascular endothelial growth factor (VEGF), resulting in abnormal vessel proliferation. Current clinical management predominantly relies on anti‐VEGF agents, which require frequent and costly injections. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has emerged as a promising strategy for permanently suppressing angiogenesis by targeting the VEGF‐related pathway. Increased research suggests that disrupting this pathway holds potential for preventing CNV progression. This review provides an overview of the aetiology, classification and pathophysiology of wet AMD, followed by a concise summary of current gene editing research using the CRISPR/Cas system via viral vector delivery strategies to target ocular pro‐angiogenic factors, including Hif‐1α, VEGF and VEGFR. The importance of timely targeting of VEGFA is emphasised and the challenges associated with gene editing therapies are also highlighted.

Age-related macular degeneration (AMD) is a typical fundus disease that affects the central vision of elderly people. It causes difficulties in everyday activities such as reading and recognizing faces. AMD can progress slowly or rapidly, and it leads to severe vision loss if left untreated. Therefore, early detection and diagnosis of AMD are crucial to prevent or delay vision impairment in the elderly. To handle this requirement, researchers are exploring deep learning-based models as an AI tool to assist ophthalmologist in AMD diagnosis. However, conducting an appropriate deep learning model for the AMD classification is challenging and cost-intensive. This research aims to evaluate the efficacy of various deep learning models for obtaining the best performance results when identifying AMD disease using retinal images. To meet this objective, the retinal images from the Department of Ophthalmology, the King Chulalongkorn Memorial Hospital, Thailand were collected for transfer learning and other publicly available datasets for testing. Then, seven deep learning models VGG19, Xception, DenseNet201, EfficientNetB7, InceptionV3, NASNetLarge, and ResNet152V2 were chosen to training for the 2-labels (Normal vs. AMD) and the 3-labels (Normal vs. Dry AMD vs. Wet AMD) classifications. From the experimental results, the DenseNet201 model with Dense block in its structure showed the best efficacy in both 2-labels and 3-labels AMD classifications since its performance always include in the Top-3 models accuracy and generalization performance measured by total accuracy and total F1-Score, respectively. Furthermore, the accuracy performance of deep learning models in Top-3 are comparable with the performance of retinal specialist. These results contribute consolidated knowledge to the process of implementation effective deep learning as production that detects AMD automatically in the clinical and enhance the quality of healthcare service.

Abstract Wet age‐related macular degeneration (wet AMD) is the most common cause of blindness, and chronic intravitreal injection of anti‐vascular endothelial growth factor (VEGF) proteins has been the dominant therapeutic approach. Less intravitreal injection and a prolonged inter‐injection interval are the main drivers behind new wet AMD drug innovations. By rationally engineering the surface residues of a model anti‐VEGF nanobody, we obtained a series of anti‐VEGF nanobodies with identical protein structures and VEGF binding affinities, while drastically different crystallization propensities and crystal lattice structures. Among these nanobody crystals, the P212121 lattice appeared to be denser and released protein slower than the P1 lattice, while nanobody crystals embedding zinc coordination further slowed the protein release rate. The polymorphic protein crystals could be a potentially breakthrough strategy for chronic intravitreal administration of anti‐VEGF proteins.

Purpose: To investigate whether a seasonal distribution of the frequency of exudative age-related macular degeneration (wet AMD) recurrences exists. Methods: In total, 129 eyes with 171 recurrences in patients suffering from wet AMD were included in the study. All the patients had been treated with intravitreal anti-VEGF injections according to Pro Re Nata treatment regimen. Recurrence was defined as the re-detection of sub-retinal fluid, intraretinal fluid, and/or sub-macular hemorrhage in optical coherence tomography scans, after at least two consecutive monthly examinations with a "dry" macula. The year was divided in three 4-month periods (zone A: June–September, zone B: October–January, and zone C: February–May) based on the weather conditions prevailing in each period. Mean temperature and hours of sunlight exposure were the main weather markers recorded. Results: Eighty-two recurrences (48%) occurred during the period June–September, 50 (29.2%) during the period October–January, and 39 (22.8%) during the period February–May (Chi-square = 17.5, p < 0.001). Among the groups, neither patients' age (78 ± 8 years A, 76 ± 7 years B, and 79 ± 8 years C, p = 0.15) nor gender status (40% men A, 36% men B, and 51% men C, p = 0.35) differed significantly. Mean temperature was 27.6 ± 1.8 °C, 15.1 ± 4.6 °C, and 16.5 ± 4.4 °C in zones A, B, and C, respectively. Hours (h) of sunlight exposure (average hours/month) were 344 ± 34 h, 188 ± 42 h, and 223 ± 57 h in zones A, B, and C. Conclusion: We demonstrated that the frequency of wet AMD recurrences is significantly elevated during the warmer months, possibly due to the higher levels of UV radiation and mean temperature. Further research is necessary to validate our findings. [ABSTRACT FROM AUTHOR]

Background: Age‐related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The hypoxia‐inducible factor‐1α (HIF‐1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to CNV pathogenesis. Previous gene editing research indicated that disrupting these genes in retinal pigment epithelial cells could have a preventive effect on CNV progression. However, no studies have yet been conducted using gene editing to disrupt VEGF signalling after CNV induction for therapeutic validation, which is critical to the clinical application of wet AMD gene editing therapies. Method: Here, we employed the single‐adeno‐associated virus‐mediated Nme2Cas9 to disrupt key molecules in VEGF signalling, Hif1α, Vegfa and Vegfr2 after inducing CNV and estimated their therapeutic effects. Results: We found that Nme2Cas9 made efficient editing in target genes up to 71.8% post 11 days in vivo. And only Nme2Cas9‐Vegfa treatment during the early stage of CNV development reduced the CNV lesion area by 49.5%, compared to the negative control, while Nme2Cas9‐Hif1α or Nme2Cas9‐Vegfr2 treatment did not show therapeutic effect. Besides, no off‐target effects were observed in Nme2Cas9‐mediated gene editing in vivo. Conclusions: This study provides proof‐of‐concept possibility of employing Nme2Cas9 for potential anti‐angiogenesis therapy in wet AMD. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD), characterized by macular retinal degeneration, poses a significant health concern due to the lack of effective treatments for prevalent dry AMD. The progression of AMD is closely linked to reactive oxygen species and Fas signaling, emphasizing the need for targeted interventions. In this study, we utilized a NaIO3-induced retinal degeneration mouse model to assess the efficacy of Fas-blocking peptide (FBP). Intravitreal administration of FBP successfully suppressed Fas-mediated inflammation and apoptosis, effectively arresting AMD progression in mice. We developed a 6R-conjugated FBP (6R-FBP) for eye drop administration. 6R-FBP, administered as an eye drop, reached the retinal region, attenuating degeneration by modulating the expression of inflammatory cytokines and blocking Fas-mediated apoptosis in rodent and rabbit NaIO3-induced retinal degeneration models to address practical concerns. Intravitreal FBP and 6R-FBP eye drops effectively reduced retinal degeneration and improved retinal thickness in rodent and rabbit models. This study highlights the therapeutic potential of FBP, particularly 6R-FBP as an eye drop, in inhibiting Fas-mediated cell signaling and protecting against retinal cell death and inflammation in dry AMD. Future investigations should explore the translational prospects of this approach in primates with eye structures comparable to those of humans.

Abstract Background Age‐related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The hypoxia‐inducible factor‐1α (HIF‐1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to CNV pathogenesis. Previous gene editing research indicated that disrupting these genes in retinal pigment epithelial cells could have a preventive effect on CNV progression. However, no studies have yet been conducted using gene editing to disrupt VEGF signalling after CNV induction for therapeutic validation, which is critical to the clinical application of wet AMD gene editing therapies. Method Here, we employed the single‐adeno‐associated virus‐mediated Nme2Cas9 to disrupt key molecules in VEGF signalling, Hif1α, Vegfa and Vegfr2 after inducing CNV and estimated their therapeutic effects. Results We found that Nme2Cas9 made efficient editing in target genes up to 71.8% post 11 days in vivo. And only Nme2Cas9‐Vegfa treatment during the early stage of CNV development reduced the CNV lesion area by 49.5%, compared to the negative control, while Nme2Cas9‐Hif1α or Nme2Cas9‐Vegfr2 treatment did not show therapeutic effect. Besides, no off‐target effects were observed in Nme2Cas9‐mediated gene editing in vivo. Conclusions This study provides proof‐of‐concept possibility of employing Nme2Cas9 for potential anti‐angiogenesis therapy in wet AMD.

Background and Objectives: The purpose was to provide the patients' perspective on the monitoring of their wet age-related macular degeneration (wet AMD) during coronavirus disease 2019 (COVID-19) and the importance of telemedicine. Materials and Methods: Wet AMD patients that underwent intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections in two Swiss ophthalmology clinics, completed two questionnaires after the first confinement due to COVID-19 in Switzerland. The first evaluated their views concerning their adherence to scheduled injections during the confinement, and the application of telemedicine in the future. The second, adapted from the National Eye Institute Visual Function Questionnaire-25, assessed their opinions on visual function change during confinement. Results: From a total of 130 patients, 8.5% responded they did not respect their assigned schedule (group 1) while 91.5% responded they did (group 2). A total of 78.7% of group 2 considered treatment reception as more relevant compared to the risk of COVID-19 contraction. During the pre-lockdown period, group 2 patients required more help from others than group 1 patients (p = 0.02). In the possibility of another lockdown, 36.3% of group 1 and 8.7% of group 2 would choose telemedicine to monitor their wet AMD (p = 0.02), 54.5% and 86.9% would rather visit the clinic (p = 0.02), while 9.0% and 4.3% would cancel their appointment, respectively. It was found that 70% of group 1 and 33.6% of group 2 would prefer to use the telemedicine services than visiting a telemedicine centre (p = 0.04). Conclusions: During circumstances similar to the COVID-19 confinement, most patients would prefer to visit the clinic. Group 1 would prefer wet AMD monitoring via telemedicine at a higher rate than group 2. [ABSTRACT FROM AUTHOR]

In recent years, there has been a captivating focus of interest in elucidating the intricate crosstalk between adiponectin (APN), a versatile fat-associated adipokine and ocular pathologies. Unveiling the intricate relationship between adipocytokine APN and its receptors (AdipoRs) with aging eye disorders has emerged as a fascinating frontier in medical research. This review article delves into this connection, illuminating the hidden influence of APN on retinal health. This comprehensive review critically examines the latest findings and breakthroughs that underscore the pivotal roles of APN/AdipoRs signaling in maintaining ocular homeostasis and protecting against eye ailments. Here, we meticulously explore the intriguing mechanisms by which APN protein influences retinal function and overall visual acuity. Drawing from an extensive array of cutting-edge studies, the article highlights APN’s multifaceted functions, ranging from anti-inflammatory properties and oxidative stress reduction to angiogenic regulation within retinal and macula tissues. The involvement of APN/AdipoRs in mediating these effects opens up novel avenues for potential therapeutic interventions targeting prevalent aging eye conditions. Moreover, this review unravels the interplay between APN signaling pathways and age-related macular degeneration (AMD). The single-cell RNA-seq results validate the expression of both the receptor isoforms (AdipoR1/R2) in retinal cells. The transcriptomic analysis showed lower expression of AdipoR1/2 in dry AMD pathogenesis compared to healthy subjects. The inhibitory adiponectin peptide (APN1) demonstrated over 75% suppression of CNV, whereas the control peptide did not exert any inhibitory effect on choroidal neovascularization (CNV). The elucidation of these relationships fosters a deeper understanding of adipose tissue’s profound influence on ocular health, presenting new prospects for personalized treatments and preventative measures. Because APN1 inhibits CNV and leakage, it can be used to treat human AMD, although the possibility to treat human AMD is in the early stage and more clinical research is needed. In conclusion, this review provides a captivating journey into the enthralling world of APN, intertwining the realms of adipose biology and ophthalmology in aging.

Age-related macular degeneration AMD is one of the leading causes of blindness in the elderly population. An advanced form of AMD known as neovascular AMD (nAMD) is implicated as the main attributor of visual loss among these patients. The hallmark feature of nAMD is the presence of neovascular structures known as choroidal neovascular membranes (CNVs), along with fluid exudation, hemorrhages, and subretinal fibrosis. These pathological changes eventually result in anatomical and visual loss. A type of proangiogenic factor known as vascular endothelial growth factor (VEGF) has been known to mediate the pathological process behind nAMD. Therefore, therapy has transitioned over the years from laser therapy that ablates the lesions to using Anti-VEGF to target the pathology directly. In this work, we provide an overview of current and emerging therapies for the treatment of nAMD. Currently approved Anti-VEGF agents include ranibizumab, aflibercept, and brolucizumab. Bevacizumab, also an Anti-VEGF agent, is used to manage nAMD even though this is an off-label use. While Anti-VEGF agents have provided a favorable prognosis for nAMD, they are associated with a substantial financial burden for patients and the healthcare system, due to their high cost as well as the need for frequent repeat treatments and visits. Emerging therapies and studies aim to extend the intervals between required treatments and introduce new treatment modalities that would improve patients' compliance and provide superior results. [ABSTRACT FROM AUTHOR]

Abstract Neovascular age-related macular degeneration (AMD) can lead to rapid, irreversible vision loss in untreated eyes. While the pathogenesis of neovascular AMD remains incompletely understood, the choriocapillaris has been hypothesized as the initial site of injury. Due to limitations of dye-based angiography, in vivo imaging of the choriocapillaris has been a longstanding challenge. However, the clinical introduction of optical coherence tomography angiography (OCTA) has enabled researchers and clinicians to noninvasively image the choriocapillaris vasculature, allowing the evaluation of the choriocapillaris in eyes with a variety of pathologies. In this perspective, we review important OCTA-based findings regarding choriocapillaris impairment in neovascular AMD and discuss limitations and future directions of OCTA technologies in the context of this disease.

Background: Most neovascular age-related macular degeneration treatments involve long-term follow-up of disease activity. Home monitoring would reduce the burden on patients and those they depend on for transport, and release clinic appointments for other patients. The study aimed to evaluate three home-monitoring tests for patients to use to detect active neovascular age-related macular degeneration compared with diagnosing active neovascular age-related macular degeneration by hospital follow-up., Objectives: There were five objectives: Estimate the accuracy of three home-monitoring tests to detect active neovascular age-related macular degeneration. Determine the acceptability of home monitoring to patients and carers and adherence to home monitoring. Explore whether inequalities exist in recruitment, participants' ability to self-test and their adherence to weekly testing during follow-up. Provide pilot data about the accuracy of home monitoring to detect conversion to neovascular age-related macular degeneration in fellow eyes of patients with unilateral neovascular age-related macular degeneration. Describe challenges experienced when implementing home-monitoring tests., Design: Diagnostic test accuracy cohort study, stratified by time since starting treatment., Setting: Six United Kingdom Hospital Eye Service macular clinics (Belfast, Liverpool, Moorfields, James Paget, Southampton, Gloucester)., Participants: Patients with at least one study eye being monitored by hospital follow-up., Reference Standard: Detection of active neovascular age-related macular degeneration by an ophthalmologist at hospital follow-up., Index Tests: KeepSight Journal: paper-based near-vision tests presented as word puzzles. MyVisionTrack®: electronic test, viewed on a tablet device. MultiBit: electronic test, viewed on a tablet device. Participants provided test scores weekly. Raw scores between hospital follow-ups were summarised as averages., Results: Two hundred and ninety-seven patients (mean age 74.9 years) took part. At least one hospital follow-up was available for 317 study eyes, including 9 second eyes that became eligible during follow-up, in 261 participants (1549 complete visits). Median testing frequency was three times/month. Estimated areas under receiver operating curves were < 0.6 for all index tests, and only KeepSight Journal summary score was significantly associated with the lesion activity (odds ratio = 3.48, 95% confidence interval 1.09 to 11.13, p  = 0.036). Older age and worse deprivation for home address were associated with lower participation (χ 2  = 50.5 and 24.3, respectively, p  < 0.001) but not ability or adherence to self-testing. Areas under receiver operating curves appeared higher for conversion of fellow eyes to neovascular age-related macular degeneration (0.85 for KeepSight Journal) but were estimated with less precision. Almost half of participants called a study helpline, most often due to inability to test electronically., Limitations: Pre-specified sample size not met; participants' difficulties using the devices; electronic tests not always available., Conclusions: No index test provided adequate test accuracy to identify lesion diagnosed as active in follow-up clinics. If used to detect conversion, patients would still need to be monitored at hospital. Associations of older age and worse deprivation with study participation highlight the potential for inequities with such interventions. Provision of reliable electronic testing was challenging., Future Work: Future studies evaluating similar technologies should consider: Independent monitoring with clear stopping rules based on test performance. Deployment of apps on patients' own devices since providing devices did not reduce inequalities in participation and complicated home testing. Alternative methods to summarise multiple scores over the period preceding a follow-up., Trial Registration: This trial is registered as ISRCTN79058224., Funding: This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/97/02) and is published in full in Health Technology Assessment ; Vol. 28, No. 32. See the NIHR Funding and Awards website for further award information.

In this study, we investigated whether cerium oxide nanoparticles (CeO2-NPs), a promising antioxidant nanomaterial, may contrast retinal vascular alterations induced by oxidative damage in vitro and in vivo. For the in vivo experiments, the light damage (LD) animal model of Age-Related Macular Degeneration (AMD) was used and the CeO2-NPs were intravitreally injected. CeO2-NPs significantly decreased vascular endothelial growth factor (VEGF) protein levels, reduced neovascularization in the deep retinal plexus, and inhibited choroidal sprouting into the photoreceptor layer. The in vitro experiments were performed on human retinal pigment epithelial (ARPE-19) cells challenged with H2O2; we demonstrated that CeO2-NPs reverted H2O2-induced oxidative stress-dependent effects on this cell model. We further investigated the RPE–endothelial cells interaction under oxidative stress conditions in the presence or absence of CeO2-NPs through two experimental paradigms: (i) treatment of human umbilical vein endothelial cells (HUVECs) with conditioned media from ARPE-19 cells, and (ii) coculture of ARPE-19 and HUVECs. In both experimental conditions, CeO2-NPs were able to revert the detrimental effect of H2O2 on angiogenesis in vitro by realigning the level of tubule formation to that of the control. Altogether, our results indicate, for the first time, that CeO2-NPs can counteract retinal neovascularization and may be a new therapeutic strategy for the treatment of wet AMD. [ABSTRACT FROM AUTHOR]

[Display omitted] Blindness in the elderly is often caused by age-related macular degeneration (AMD). The advanced type of AMD known as neovascular AMD (nAMD) has been linked to being the predominant cause of visual impairment in these people. Multiple neovascular structures including choroidal neovascular (CNV) membranes, fluid exudation, hemorrhages, and subretinal fibrosis, are diagnostic of nAMD. These pathological alterations ultimately lead to anatomical and visual loss. It is known that vascular endothelial growth factor (VEGF), a type of proangiogenic factor, mediates the pathological process underlying nAMD. Therefore, various therapies have evolved to directly target the disease. In this review article, an attempt has been made to discuss general explanations about this disease, all common treatment methods based on anti-VEGF drugs, and the use of drug delivery systems in the treatment of AMD. Initially, the pathophysiology, angiogenesis, and different types of AMD were described. Then we described current treatments and future treatment prospects for AMD and outlined the advantages and disadvantages of each. In this context, we first examined the types of therapeutic biomolecules and anti-VEGF drugs that are used in the treatment of AMD. These biomolecules include aptamers, monoclonal antibodies, small interfering RNAs, microRNAs, peptides, fusion proteins, nanobodies, and other therapeutic biomolecules. Finally, we described drug delivery systems based on liposomes, nanomicelles, nanoemulsions, nanoparticles, cyclodextrin, dendrimers, and composite vehicles that are used in AMD therapy. [ABSTRACT FROM AUTHOR]

Background and Objectives: The purpose was to provide the patients’ perspective on the monitoring of their wet age-related macular degeneration (wet AMD) during coronavirus disease 2019 (COVID-19) and the importance of telemedicine. Materials and Methods: Wet AMD patients that underwent intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections in two Swiss ophthalmology clinics, completed two questionnaires after the first confinement due to COVID-19 in Switzerland. The first evaluated their views concerning their adherence to scheduled injections during the confinement, and the application of telemedicine in the future. The second, adapted from the National Eye Institute Visual Function Questionnaire-25, assessed their opinions on visual function change during confinement. Results: From a total of 130 patients, 8.5% responded they did not respect their assigned schedule (group 1) while 91.5% responded they did (group 2). A total of 78.7% of group 2 considered treatment reception as more relevant compared to the risk of COVID-19 contraction. During the pre-lockdown period, group 2 patients required more help from others than group 1 patients (p = 0.02). In the possibility of another lockdown, 36.3% of group 1 and 8.7% of group 2 would choose telemedicine to monitor their wet AMD (p = 0.02), 54.5% and 86.9% would rather visit the clinic (p = 0.02), while 9.0% and 4.3% would cancel their appointment, respectively. It was found that 70% of group 1 and 33.6% of group 2 would prefer to use the telemedicine services than visiting a telemedicine centre (p = 0.04). Conclusions: During circumstances similar to the COVID-19 confinement, most patients would prefer to visit the clinic. Group 1 would prefer wet AMD monitoring via telemedicine at a higher rate than group 2.

Purpose: To investigate how modulating ocular sympathetic activity affects progression of choroidal neovascularization (CNV), a hallmark feature of wet age-related macular degeneration (AMD). Methods: In the first of two studies, Brown Norway rats underwent laser-induced CNV and were assigned to one of the following groups: daily eye drops of artificial tears (n = 10; control group); daily eye drops of the β-adrenoreceptor agonist isoproterenol (n = 10); daily eye drops of the β-adrenoreceptor antagonist propranolol (n = 10); sympathetic internal carotid nerve (ICN) transection 6 weeks prior to laser-induced CNV (n = 10). In the second study, rats underwent laser-induced CNV followed by ICN transection at different time points: immediately after the laser injury (n = 6), 7 days after the laser injury (n = 6), and sham surgery 7 days after the laser injury (n = 6; control group). All animals were euthanized 14 days after laser application. CNV development was quantified with fluorescein angiography and optical coherence tomography (in vivo), as well as lesion volume analysis using 3D confocal reconstruction (postmortem). Angiogenic growth factor protein levels in the choroid were measured with ELISA. Results: In the first study, blocking ocular sympathetic activity through pharmacological or surgical manipulation led to a 75% or 70% reduction in CNV lesion volume versus the control group, respectively (P < 0.001). Stimulating ocular sympathetic activity with isoproterenol also led to a reduction in lesion volume, but only by 27% versus controls (P < 0.05). VEGF protein levels in the choroid were elevated in the three treatment groups (P < 0.01). In the second study, fluorescein angiography and CNV lesion volume analysis indicated that surgically removing the ocular sympathetic supply inhibited progression of laser-induced CNV, regardless of whether ICN transection was performed on the same day or 7 days after the laser injury. Conclusion: Surgical and pharmacological block of ocular sympathetic activity can inhibit progression of CNV in a rat model. Therefore, electrical block of ICN activity could be a potential bioelectronic medicine strategy for treating wet AMD. [ABSTRACT FROM AUTHOR]

Purpose: To investigate how modulating ocular sympathetic activity affects progression of choroidal neovascularization (CNV), a hallmark feature of wet age-related macular degeneration (AMD).Methods: In the first of two studies, Brown Norway rats underwent laser-induced CNV and were assigned to one of the following groups: daily eye drops of artificial tears (n = 10; control group); daily eye drops of the β-adrenoreceptor agonist isoproterenol (n = 10); daily eye drops of the β-adrenoreceptor antagonist propranolol (n = 10); sympathetic internal carotid nerve (ICN) transection 6 weeks prior to laser-induced CNV (n = 10). In the second study, rats underwent laser-induced CNV followed by ICN transection at different time points: immediately after the laser injury (n = 6), 7 days after the laser injury (n = 6), and sham surgery 7 days after the laser injury (n = 6; control group). All animals were euthanized 14 days after laser application. CNV development was quantified with fluorescein angiography and optical coherence tomography (in vivo), as well as lesion volume analysis using 3D confocal reconstruction (postmortem). Angiogenic growth factor protein levels in the choroid were measured with ELISA.Results: In the first study, blocking ocular sympathetic activity through pharmacological or surgical manipulation led to a 75% or 70% reduction in CNV lesion volume versus the control group, respectively (P < 0.001). Stimulating ocular sympathetic activity with isoproterenol also led to a reduction in lesion volume, but only by 27% versus controls (P < 0.05). VEGF protein levels in the choroid were elevated in the three treatment groups (P < 0.01). In the second study, fluorescein angiography and CNV lesion volume analysis indicated that surgically removing the ocular sympathetic supply inhibited progression of laser-induced CNV, regardless of whether ICN transection was performed on the same day or 7 days after the laser injury.Conclusion: Surgical and pharmacological block of ocular sympathetic activity can inhibit progression of CNV in a rat model. Therefore, electrical block of ICN activity could be a potential bioelectronic medicine strategy for treating wet AMD.

Laser-induced choroidal neovascularization (L-CNV) in murine models is a standard method for assessing therapies, genetics, and mechanisms relevant to the blinding eye disease neovascular or “wet” age-related macular degeneration. The ex vivo evaluation of these lesions involves confocal microscopy analysis. In vivo evaluation via optical coherence tomography (OCT) has previously been established and allows longitudinal assessment of lesion development. However, to produce robust data, evaluation of many lesions may be required, which can be a slow, arduous process. A prior, manual method for quantifying these lesions as ellipsoids from orthogonal OCT images was effective but time consuming. We therefore developed an OCT lesion quantification that is simplified, streamlined, and less time-consuming.

Neovascular age-related macular degeneration (AMD) can lead to rapid, irreversible vision loss in untreated eyes. While the pathogenesis of neovascular AMD remains incompletely understood, the choriocapillaris has been hypothesized as the initial site of injury. Due to limitations of dye-based angiography, in vivo imaging of the choriocapillaris has been a longstanding challenge. However, the clinical introduction of optical coherence tomography angiography (OCTA) has enabled researchers and clinicians to noninvasively image the choriocapillaris vasculature, allowing the evaluation of the choriocapillaris in eyes with a variety of pathologies. In this perspective, we review important OCTA-based findings regarding choriocapillaris impairment in neovascular AMD and discuss limitations and future directions of OCTA technologies in the context of this disease. [ABSTRACT FROM AUTHOR]

Jaycob Avaylon,1 Sol Lee,2 Ron P Gallemore2 1California Northstate University, College of Medicine, Elk Grove, CA, USA; 2Retina Macula Institute, Torrance, CA, USACorrespondence: Ron P GallemoreRetina Macula Institute, 4201 Torrance Blvd., Ste 220, Torrance, CA 90503, USATel +1 310 413-7020Email rongallemoremd@gmail.comPurpose: To report a case series of initial responses to intravitreal brolucizumab in patients already undergoing anti-VEGF therapy for wet age-related macular degeneration.Case Series: Six eyes (6 patients) with a history of wet age-related macular degeneration presented with either decline in vision or no improvement while undergoing treatment with anti-VEGF therapy – aflibercept or bevacizumab. Patients were switched to intravitreal brolucizumab. Four weeks post-injection, there was no significant change in visual acuity. Optical coherence tomography scans were taken and improved IRF/SRF, central macular thickness and average pericentral thickness were observed in all 6 patients. No serious adverse reactions were observed, including signs of vasculitis or increase in anterior chamber cell count at the 4-week follow-up for all 6 patients.Conclusion: Intravitreal brolucizumab appears to be a safe and limitedly effective option for patients with recalcitrant CNV from wet AMD.Keywords: macular degeneration, anti-VEGF, brolucizumab, wet AMD, choroidal neovascularization

Introduction/Objective. The study aims to analyze the thickness of both the ganglion cell layer and the inner plexiform layer (GCL + IPL) among patients suffering from dry and wet form of age-related macular degeneration (AMD). Methods. One hundred ninety-five patients with AMD participated in the study, along with 94 healthy individuals (mean age 75.2 ± 7.8 years; range 55–86). They were divided into three groups: the first group, or group I, included 100 patients suffering from wet AMD; the second group, or group II, included 95 patients afflicted with dry AMD; the final 94 patients made up the control group, group III, of healthy individuals without systemic or ocular diseases. Measurements such as the average macular thickness, the average and minimum GCL + IPL thickness, and the GCL + IPL thickness in all six sectors were obtained by Cirrus spectral-domain optical coherence tomography (SD-OCT, Carl Zeiss Meditec, Inc., Dublin, CA, USA). SPSS version 20.0 was used to analyze the data, while the level of statistical significance was set at p < 0.05. Results. In the case of patients with wet AMD, the average value for GCL + IPL thickness was 43.13 μm, for patients with dry AMD the value was 66.73 μm, and the average thickness measured for the control group was 86.23 μm. There was a statistically significant difference between the average GCL + IPL and minimum GCL + IPL thicknesses between the groups (p < 0.001). Lower values were noted for patients with wet AMD (p < 0.001) than those with dry AMD. In the latter, the average GCL + IPL and the minimum GCL + IPL thicknesses were lower than those of the healthy participants, at a level of statistical significance (p < 0.001). Conclusion. Participants with AMD exhibited thinner GCL + IPL than the healthy participants, as did the participants with wet AMD when compared to the participants with dry AMD.

Age-related macular degeneration AMD is one of the leading causes of blindness in the elderly population. An advanced form of AMD known as neovascular AMD (nAMD) is implicated as the main attributor of visual loss among these patients. The hallmark feature of nAMD is the presence of neovascular structures known as choroidal neovascular membranes (CNVs), along with fluid exudation, hemorrhages, and subretinal fibrosis. These pathological changes eventually result in anatomical and visual loss. A type of proangiogenic factor known as vascular endothelial growth factor (VEGF) has been known to mediate the pathological process behind nAMD. Therefore, therapy has transitioned over the years from laser therapy that ablates the lesions to using Anti-VEGF to target the pathology directly. In this work, we provide an overview of current and emerging therapies for the treatment of nAMD. Currently approved Anti-VEGF agents include ranibizumab, aflibercept, and brolucizumab. Bevacizumab, also an Anti-VEGF agent, is used to manage nAMD even though this is an off-label use. While Anti-VEGF agents have provided a favorable prognosis for nAMD, they are associated with a substantial financial burden for patients and the healthcare system, due to their high cost as well as the need for frequent repeat treatments and visits. Emerging therapies and studies aim to extend the intervals between required treatments and introduce new treatment modalities that would improve patients’ compliance and provide superior results.

Purpose: The aim of the present cross-sectional real-world study is to evaluate the impact of switch of anti-VEGF agent from ranibizumab to aflibercept on visual acuity, treatment frequency and retinal morphology after 12 months in eyes with ongoing chronic treatment for wet age-related macular degeneration (AMD) compared to eyes not subjected to switch of anti-VEGF agent. Methods: Data was obtained retrospectively from the Swedish Macular Register, spectral-domain optical coherence tomography (OCT) images and electronic patient charts. All eyes included were treated in the same clinical setting at the Department of Ophthalmology at the county hospital of Västmanland in Västerås, Sweden. Results: In total, 282 and 359 eyes were included in the non-switch and switch cohorts, respectively. The cohorts were well balanced. Visual acuity remained stable during the observation period in both cohorts of eyes. The number of anti-VEGF treatments slowly declined over time in both cohorts of eyes and, consequently, the treatment intervals increased during the observation period. In eyes subjected to switch of anti-VEGF agent, planned treatment interval at 12 months was 7.6 (mean; SD 2.9) weeks compared to 6.8 (mean; SD 2.7) in the non-switch cohort (P = 0.001). OCT images demonstrated lower prevalence of intraretinal and subretinal fluid as well as pigment epithelial detachment at 12 months in eyes subjected to switch of anti-VEGF agent compared to non-switch eyes. Conclusion: Switch of anti-VEGF agent from ranibizumab to aflibercept did not affect visual function whereas improvement in retinal morphology was observed. These findings suggest a beneficial effect of switching from ranibizumab to aflibercept in eyes with ongoing chronic anti-VEGF treatment irrespective of previous response to ranibizumab. Longer follow-up is required to further evaluate the potential clinical significance of this finding. [ABSTRACT FROM AUTHOR]

The wet form of age-related macular degeneration is characterized by neovascular pathologies that, if untreated, can result in edemas followed by rapid vision loss. Inhibition of vascular endothelial growth factor (VEGF) has been used to successfully treat neovascular pathologies of the eye. Nonetheless, some patients require frequent intravitreal injections of anti-VEGF drugs, increasing the burden and risk of complications from the procedure to affected individuals. Recombinant adeno-associated virus (rAAV)-mediated expression of anti-VEGF proteins is an attractive alternative to reduce risk and burden to patients. However, controversy remains as to the safety of prolonged VEGF inhibition in the eye. Here, we show that two out of four rAAV serotypes tested by intravitreal delivery to express the anti-VEGF drug conbercept lead to a dose-dependent vascular sheathing pathology that is characterized by immune cell infiltrates, reminiscent of vasculitis in humans. We show that this pathology is accompanied by increased expression in vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), both of which promote extravasation of immune cells from the vasculature. While formation of the vascular sheathing pathology is prevented in immunodeficient Rag-1 mice that lack B and T cells, increased expression of VACM1 and ICAM1 still occurs, indicating that inhibition of VEGF function leads to expression changes in cell adhesion molecules that promote extravasation of immune cells. Importantly, a 10-fold lower dose of one of the vectors that cause a vascular sheathing pathology is still able to reduce edemas resulting from choroidal neovascularization without causing any vascular sheathing pathology and only a minimal increase in VCAM1 expression. The data suggest that treatments of neovascular eye pathologies with rAAV-mediated expression of anti VEGF drugs can be developed safely. However, viral load needs to be adjusted to the tropisms of the serotype and the expression pattern of the promoter. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to assess the follow-up and treatment outcomes of eyes with wet age-related macular degeneration (wet AMD) for two years in a real-life clinical practice setting. Methods: In total, 37 eyes of 37 patients with wet AMD treated with 0.5 mg of intravitreal ranibizumab as needed and with at least 2 years of follow-up were retrospectively evaluated. Analyses included best-corrected visual acuity (BCVA) and central foveal thickness measurements (CFT) by optical coherence tomography at baseline, sixth month, first year, and second year along with the number of injections and follow-up visits. Results: A total of 37 eyes of 37 patients (23 women and 14 men) with a mean age of 74.6±7.9 years were evaluated in this study. The mean BCVAs were 58.1±26.7 letters at baseline, 59.9±29.3 letters at the sixth month, 58.8±28.9 letters at the first year, and 59.2±28.5 letters at the second year. No statistically significant difference in BCVA was detected among the scores at baseline, sixth month, first year, and second year (p=0.214, 0.791, and 0.945, respectively). The CFTs averaged 340.6±89.7 μm at baseline, 316.9±87.8 μm at the sixth month, 330.2±95.8 μm at the first year, and 323.4±97.2 μm at the second year. Only the CFT at sixth month showed a statistically significant improvement over the baseline value (p=0.031). Conclusion: Considering the number of injections and follow-up visits, along with the course of outcomes in BCVA and CFT, our real-life outcomes remained far below the outcomes reported in pivotal randomized clinical trials. However, recent papers related to real-life performance in wet AMD show similar results to those of our study. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is the most common cause of severe visual impairment in older adults in the developed world. Especially neovascular AMD, characterized by rapid progression and a significant reduction in visual acuity, until recently was a therapeutic challenge. The last 15 years have been a period of development of new diagnostic and treatment possibilities. The paper presents recommendations of the Polish Ophthalmological Society for the management of neovascular age-related macular degeneration based on the latest publications. [ABSTRACT FROM AUTHOR]

In this study, we investigated whether cerium oxide nanoparticles (CeO2-NPs), a promising antioxidant nanomaterial, may contrast retinal vascular alterations induced by oxidative damage in vitro and in vivo. For the in vivo experiments, the light damage (LD) animal model of Age-Related Macular Degeneration (AMD) was used and the CeO2-NPs were intravitreally injected. CeO2-NPs significantly decreased vascular endothelial growth factor (VEGF) protein levels, reduced neovascularization in the deep retinal plexus, and inhibited choroidal sprouting into the photoreceptor layer. The in vitro experiments were performed on human retinal pigment epithelial (ARPE-19) cells challenged with H2O2; we demonstrated that CeO2-NPs reverted H2O2-induced oxidative stress-dependent effects on this cell model. We further investigated the RPE–endothelial cells interaction under oxidative stress conditions in the presence or absence of CeO2-NPs through two experimental paradigms: (i) treatment of human umbilical vein endothelial cells (HUVECs) with conditioned media from ARPE-19 cells, and (ii) coculture of ARPE-19 and HUVECs. In both experimental conditions, CeO2-NPs were able to revert the detrimental effect of H2O2 on angiogenesis in vitro by realigning the level of tubule formation to that of the control. Altogether, our results indicate, for the first time, that CeO2-NPs can counteract retinal neovascularization and may be a new therapeutic strategy for the treatment of wet AMD.

Toke Bek, Sidsel Ehlers Klug Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark Purpose: Randomized clinical trials studying the effects of VEGF inhibition on wet age-related macular degeneration (wAMD) are designed so that the effects of individually varying risk factors on the treatment response are eliminated. The influence of these risk factors can be studied in large data sets from real-life experience.Patients and methods: All 2,255 patients diagnosed with wAMD requiring anti-VEGF treatment in at least one eye over more than 9 years in a defined Danish population with 0.9 million inhabitants were studied. The predictive value of eye laterality, sex, current smoking status, type of anti-VEGF compound, membrane position, membrane type, leakage area, number of injections, number of visits, age, time to follow-up, visual acuity, and central retinal thickness (CRT) at baseline on change in CRT after three monthly injections with anti-VEGF compound followed by treatment pro re nata for up to 12 months was assessed.Results: After 12 months, 67 patients had died, 903 had had stable CRT for at least 6 months, and 1,285 patients had not achieved stable CRT. The reduction in CRT was -84.8±118.3 µm, whereas the increase in visual acuity was 2.2±14.7 Early Treatment Diabetic Retinopathy Study letters. The risk factors included contributed to 64% of the variation in CRT reduction. High age and high CRT at baseline predicted high CRT reduction, whereas more injections, treatment with ranibizumab, and male sex predicted a low CRT reduction.Conclusion: Age, sex, and type of anti-VEGF medication can be used to plan treatment and inform patients about the expected response of anti-VEGF treatment in wAMD. Keywords: wet AMD, anti-VEGF treatment, risk factors, real-life experience

In developed countries, age-related macular degeneration (AMD), a retinal disease, is the main cause of vision loss in the elderly. Optical Coherence Tomography (OCT) is currently the gold standard for assessing individuals for initial AMD diagnosis. In this paper, we look at how OCT imaging can be used to diagnose AMD. Our main aim is to examine and compare automated computer-aided diagnostic (CAD) systems for diagnosing and grading of AMD. We provide a brief summary, outlining the main aspects of performance assessment and providing a basis for current research in AMD diagnosis. As a result, the only viable alternative is to prevent AMD and stop both this devastating eye condition and unwanted visual impairment. On the other hand, the grading of AMD is very important in order to detect early AMD and prevent patients from reaching advanced AMD disease. In light of this, we explore the remaining issues with automated systems for AMD detection based on OCT imaging, as well as potential directions for diagnosis and monitoring systems based on OCT imaging and telemedicine applications.

This study explored the expression of several miRNAs reported to be deregulated in age-related macular degeneration (AMD). Total RNA was isolated from sera from patients with dry AMD (n = 12), wet AMD (n = 14), and controls (n = 10). Forty-two previously investigated miRNAs were selected based on published data and their role in AMD pathogenesis, such as angiogenic and inflammatory effects, and were co-analysed using a miRCURY LNA miRNA SYBR® Green PCR kit via quantitative real-time polymerase chain reaction (qRT-PCR) to validate their presence. Unsupervised hierarchical clustering indicated that AMD serum specimens have a different miRNA profile to healthy controls. We successfully validated the differentially regulated miRNAs in serum from AMD patients versus controls. Eight miRNAs (hsa-let-7a-5p, hsa-let-7d-5p, hsa-miR-23a-3p, hsa-miR-301a-3p, hsa-miR-361-5p, hsa-miR-27b-3p, hsa-miR-874-3p, hsa-miR-19b-1-5p) showed higher expression in the serum of dry AMD patients than wet AMD patients and compared with healthy controls. Increased quantities of certain miRNAs in the serum of AMD patients indicate that these miRNAs could potentially serve as diagnostic AMD biomarkers and might be used as future AMD treatment targets. The discovery of significant serum miRNA biomarkers in AMD patients would provide an easy screening tool for at-risk populations.

Background and objectives: The aim of this study was to evaluate the therapeutic results in patients with exudative AMD treated with ranibizumab and aflibercept intravitreal injections over a two-year observation period. Materials and methods: A retrospective observational study was conducted in a clinical hospital on a group of patients who randomly qualified for treatment with Aflibercept (group A) and Ranibizumab (group B) as part of the Polish National Health Fund Medical Program for exudative AMD. Group A consisted of 90 patients, and group B contained 54 patients. The choice of drug in a patient depended solely on the availability of the medication at the time. Before each injection, best corrected visual acuity (BCVA) on the ETDRS scale and central retinal thickness (CRT) were assessed using optical coherence tomography (OCT). Patients from both groups were treated in the first year of treatment with a rigid scheme of 3 doses of 2.0 mg Aflibercept (group A) and 0.5 mg Ranibizumab (group B) at monthly intervals, followed by 4 doses at bimonthly intervals. In the second year, a “pro re nata” scheme was applied. The aim was to evaluate changes in BCVA and CRT after three injections, after 7 injections (about 12 months), and after the second year of therapy (24 months) with reference to the baseline and to compare the effectiveness of the medications. The influences of the following factors were studied: age, gender, initial BCVA, and initial CRT, as well as the number of injections received. Results: No significant statistical differences were found between patients receiving Aflibercept and Ranibizumab therapy in terms of achieving improved visual acuity and reducing retinal thickness after two years of therapy. Conclusions: Both aflibercept and ranibizumab were found to be effective for treating exudative AMD.