Neovascular Age-related Macular Degeneration Patients Research Articles

Deep Learning in Neovascular Age-Related Macular Degeneration.

Background and objectives: Age-related macular degeneration (AMD) is a complex and multifactorial condition that can lead to permanent vision loss once it progresses to the neovascular exudative stage. This review aims to summarize the use of deep learning in neovascular AMD. Materials and Methods: Pubmed search. Results: Deep learning has demonstrated effectiveness in analyzing structural OCT images in patients with neovascular AMD. This review outlines the role of deep learning in identifying and measuring biomarkers linked to an elevated risk of transitioning to the neovascular form of AMD. Additionally, deep learning techniques can quantify critical OCT features associated with neovascular AMD, which have prognostic implications for these patients. Incorporating deep learning into the assessment of neovascular AMD eyes holds promise for enhancing clinical management strategies for affected individuals. Conclusion: Several studies have demonstrated effectiveness of deep learning in assessing neovascular AMD patients and this has a promising role in the assessment of these patients.

Correlations Between the Neutrophil-Lymphocyte Ratio, Platelet-Lymphocyte Ratio, and Serum Lipid Fractions With Neovascular Age-Related Macular Degeneration.

Introduction Age-related macular degeneration, a chronic and progressive disease, is one of the leading causes of vision loss globally among the elderly population. Multiple hypotheses have been proposed regarding its pathogenesis, including the presence of lipid metabolism alteration. Dysfunctional lipid handling within retinal pigment epithelial cells has been implicated in the accumulation of lipofuscin and subsequent induction of oxidative stress and inflammation, all contributing to retinal degeneration. The present study aims to comparatively analyze the serum lipid fractiondistributions in patients with neovascular age-related macular degeneration (AMD) and controls. Materials and methods A retrospective study was carried out between January 2021 and December 2023 on 91 naïve patients with neovascular AMD and 90 controlsadmitted for routine cataract surgery. All subjects underwent a comprehensive ophthalmological exam, including ophthalmoscopy and optical coherence tomography (OCT) with central macular thickness (CMT) measurement. A complete blood count with differential and lipid fractions values was analyzed. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were comparatively analyzed between the control group and the test group. Results The groups were comparable in terms of age (73.84 ±7.52 years for the neovascular AMD group vs 72.1±10.92 years in controls; p=0.8) and gender distribution (p=0.243). The mean NLR and PLR values were slightly higher in the AMD groupbut not statistically significant (p=0.51, p>0.99, respectively). Comparative analysis of lipid profile fractions showed significantly higher HDL-C values in the exudative AMD group compared to normal subjects (61.27±19.4 mg/dL vs 50.99±7.86 mg/dL, p=0.006). Also, the proportion of subjects with HDL-C>60 mg/dL was higher in the exudative AMD group (p=0.014). There were no significant differences in total cholesterol (189.77±53.39 mg/dL vs 190.43±37.84 mg/dL, p=0.681), LDL-C, and TG. Logistic regression analysis showed that serum HDL-C and HDL-C values >60 mg/dL are significantly associated factors with neovascular AMD. However, there is no statistical correlation between the values of these biochemical parameters and visual acuity or CMT in the neovascular AMD patient group. Conclusions There were no correlations between NLR and PLR with neovascular AMD in the study group. Higher HDL-C valuesexceeding 60 mg/dL were associated with neovascular age-related macular degeneration and could represent a possible therapeutic target in neovascular AMD.

Oxidative Stress, Persistent Inflammation and Blood Coagulation Alterations in Serum Proteome of Patients with Neovascular Age-Related Macular Degeneration.

Neovascular age-related macular degeneration (AMD) is a major cause of irreversible blindness in elderly populations in developed countries. AMD's etiopathology is multifactorial, with strong environmental and genetic components, but the exact molecular pathomechanisms underlying the disease are still unknown. In this study, we analyzed blood serum collected from 74 neovascular AMD patients and 58 healthy controls to identify proteins that may serve as potential biomarkers and expand our knowledge about the etiopathogenesis of the disease. The study revealed 17 differentially expressed proteins-11 up-regulated and 6 down-regulated-in neovascular AMD, which are involved in the biological processes previously linked with the disease-oxidative stress and persistent inflammation, impaired cellular transport, lipid metabolism and blood coagulation. In conclusion, the differences in the expressions of the proteins identified in this study may contribute to our understanding of the mechanisms underlying AMD and possibly serve in future as promising biomarkers.

Evaluation of the Effect of Age-Related Macular Degeneration Type And Stage on the Risk of Parkinson’s Disease

The aim of the study was to investigate the distance between Parkinson's Disease (PD) and Age-Related Macular Degeneration (AMD) type and stage.. Our prospective study, the dry-type AMD group consisted of 296 patients with early and 284 patients with late-stage. The neovascular AMD group included 285 early and 277 late-stage patients. The control group consisted of 300 patients. AMD patients were grouped as dry and neovascular type and early and late stage. The patients were questioned about the use of drugs for PD, and the use was recorded as having the disease. If any of the complaints seen in the PD were present, the patient was referred to a neurologist. PD was detected in 1% of the control group and 4.6% in the neovascular type AMD group, and this difference was significant (p:0.04). This difference was present in both the early (%4.5) and late-stage (%4.6 ) (p:0.04, p:0.04). PD was determined 3.78 times greater among neovascular AMD patients(p:0.03), and significant association was present in both early (3.72 times) and late-stage (3.82 times) (p:0.03, p:0.03). In the dry-type AMD group 2.7% PD was detected and there was no statistical difference (p>0.05). This difference was not significant in the early stage (%2.3) or late-stage (%2.8) and also there was no association with dry-type AMD (p>0.05). Also, unilateral and bilateral involvement in AMD was not associated with PD (p>0.05). Our study revealed the association between both early and late neovascular AMD and PD. However, any significant relationship was not detected in terms of both unilateral and bilateral involvement.

Central retinal artery occlusion after intravitreal brolucizumab injection for treatment-naïve neovascular age-related macular degeneration; a case report

BackgroundTo report a case of central retinal artery occlusion (CRAO) after intravitreal injection of brolucizumab for a treatment-naïve neovascular age-related macular degeneration (nAMD) patient without comorbid cardiovascular disease history.Case presentationA 79-year-old Asian male without a cardiovascular disease history such as diabetes or hypertension underwent three times of monthly consecutive intravitreal brolucizumab injections for treatment of progressed nAMD in his left eye. Two days after the third injection, the patient presented with acute painless visual loss. Typical retinal whitening with a cherry red spot was observed on the fundus photograph, and retinal swelling with hyper-reflectivity was also identified on the optical coherence tomography (OCT) scan. On the fundus fluorescein angiography, arm-to-retina time and arteriovenous transit time were remarkedly delayed, but clinical findings suggesting an intraocular inflammation (IOI) were not observed. Therefore, CRAO was diagnosed, and anterior chamber paracentesis was administrated immediately. However, there had been no improvement in visual acuity during the follow-up period of three months, despite prolonged oral steroid and anti-platelet agent medication.ConclusionsIn rare cases, patients without cardiovascular comorbidities can develop CRAO after intravitreal brolucizumab injection without gross evidence of IOI. Therefore, CRAO should always be in consideration and careful observation is required after intravitreal brolucizumab injection for nAMD patients with old age, even if the patient does not have any other cardiovascular disease history.

Visual outcomes of intraocular inflammation after brolucizumab injection in Japanese patients with neovascular age-related macular degeneration.

This study investigates the visual outcomes of neovascular age-related macular degeneration (nAMD) patients who developed intraocular inflammation (IOI) after intravitreal brolucizumab injection (IVBr). We studied 285 eyes of 279 cases diagnosed with nAMD and focused on 18 eyes (6.3%) of 17 cases which developed IOI after IVBr. IVBr was performed either on the initial treatment or for switching of other anti-vascular endothelial growth factor agents during January 2020 to December 2021. We evaluated clinical features and the course of treatment of a 6-month follow-up after IOI occurred. Of 17 cases, 9 cases were male, 8 cases were female. Baseline logarithm of the minimum angle of resolution(logMAR) best-corrected visual acuity (BCVA) was 0.36, BCVA before IOI occurred was 0.30, and BCVA when IOI occurred was 0.43. 16 eyes (88.9%) had symptoms such as visual loss or floaters when IOI occurred. On the other hand, the remaining 2 eyes (11.1%) had no symptoms. 11 eyes (61.1%) had only IOI, while the remaining 7 eyes (38.9%) had IOI and perivascular sheathing. Steroid sub-tenon injection was performed on 1 eye (5.6%), steroid eye drops were used in 11 eyes (61.1%), and 6 eyes (33.3%) were followed-up without treatment. Neovascular AMD recurred in 16 eyes (88.9%) after IOI occurred and were treated with aflibercept. VA at 3 and 6 months after IOI occurred were significantly improved to 0.34 and 0.30, respectively (P = 0.09 at 3 months and P = 0.02 at 6 months). The symptoms of patients were improved in all cases. We were able to stop steroid treatment in all cases. IOI occurred in 6.3% of nAMD patients after IVBr treatment. All of which showed significant improvement from logMAR of 0.43 to 0.30 with steroid treatment or without any treatment. We should consider the possibility of IOI after IVBr as a complication, however, they have a relatively good prognosis if treated at an early stage.

Thrombospondin-1, BIM and CFH polymorphisms and response to anti-VEGF treatment in neovascular age- related macular degeneration patients.

Age-related macular degeneration (AMD) is a vision threatening disease in older adults. Anti-VEGF treatment is effective for the majority of neovascular AMD (nAMD) patients, although approximately 30% of nAMD patients have an incomplete response for unknown reasons. Here we assessed the contribution of single nucleotide polymorphisms (SNPs) in key angioinflammatory regulatory genes in nAMD patients with an incomplete response compared to those responsive to anti-VEGF treatment. A total of 25 responsive and 30 nAMD patients with an incomplete response to anti-vascular endothelial growth factor (anti-VEGF) treatment were examined for known SNPs that impact the structure and function of thromobospondin-1 (TSP1), Bcl-2-interacting mediator of cell death (BIM) and complement factor H (CFH). Plasma levels of C-C motif chemokine ligand 2 (CCL2/MCP1), TSP1 and VEGF were assessed by ELISA. Patients responsive to anti-VEGF treatment showed a significant increase in the TSP1 rs2228262 AA allele and a trend for the BIM (rs724710) CT allele. Consistent with previous reports, 42% of the patients responsive to anti-VEGF expressed the CC allele for CFH rs1061170. Although the CFH TT allele had similarly low prevalence in both groups, the TC allele tended to be more prevalent in patients with an incomplete response. Patients with an incomplete response also had increased plasma CCL2/MCP1 levels, consistent with the role increased inflammation has in the pathogenesis of nAMD. Our studies point to new tools to assess the potential responsiveness of nAMD patients to anti-VEGF treatment and suggest the potential use of anti-CCL2 for treatment of nAMD patients with an incomplete response to anti-VEGF.

REDUCING TREATMENT BURDEN FOR AGE-RELATED MACULAR DEGENERATION PATIENTS: A SYSTEMATIC REVIEW OF RANIBIZUMAB PORT DELIVERY SYSTEM

Introduction and Objective: Ranibizumab port delivery system (PDS) is a newly developed method that provides a continuous, long-term supply of ranibizumab into the vitreous, reducing the burden of monthly intravitreal injection visits for neovascular age-related macular degeneration (nAMD) patients. This review aims to evaluate the efficacy and safety of ranibizumab PDS in nAMD. 
 Methods: An extensive literature search was performed on 4 online databases: PubMed, Cochrane, ProQuest, and ScienceDirect. The inclusion criteria are human studies comparing ranibizumab port delivery system and intravitreal ranibizumab, English language, with full-text journal available. The main outcome measurements are best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters, central foveal thickness (CFT), and adverse events.
 Result: Two randomized controlled trials (RCTs) with a total of 635 adults were evaluated. At week 96, ranibizumab PDS reported observed mean BCVA changes from baseline (-1.0; +4.2; ETDRS letters) compared to monthly intravitreal ranibizumab (-1.1; +6.1; ETDRS letters). However, there was an increase in mean CFT changes from baseline (+9.9; -15.3 vs ?1.3; -21.3, µm) and more severe adverse events frequency (22; 4 vs 4; 0) with ranibizumab PDS versus monthly intravitreal ranibizumab, respectively. 
 Conclusion: Ranibizumab PDS showed comparable visual outcomes to intravitreal ranibizumab while demonstrating marginally inferior anatomical outcomes and higher incidence of severe adverse effects. Despite this, with fewer treatment visits required for up to 24 weeks, ranibizumab PDS can potentially reduce the treatment burden in nAMD patients with poor compliance. Further studies are needed to provide better patient eligibility guidelines and recommendations for adverse event management of ranibizumab PDS.

Reducing Treatment Burden for Age-Related Macular Degeneration Patients: A Systematic Review of Ranibizumab Port Delivery System

Introduction & ObjectivesRanibizumab port delivery system (PDS) is a newly developed method that provides a continuous,long-term supply of ranibizumab into the vitreous, reducing the burden of monthly intravitrealinjection visits for neovascular age-related macular degeneration (nAMD) patients. This review aimsto evaluate the efficacy and safety of ranibizumab PDS in nAMD.
 MethodsAn extensive literature search was performed on 4 online databases: PubMed, Cochrane, ProQuest,and ScienceDirect. The inclusion criteria are human studies comparing ranibizumab port deliverysystem and intravitreal ranibizumab, English language, with full-text journal available. The mainoutcome measurements are best-corrected visual acuity (BCVA) in Early Treatment DiabeticRetinopathy Study (ETDRS) letters, central foveal thickness (CFT), and adverse events.
 ResultsTwo randomized controlled trials (RCTs) with a total of 638 adults were evaluated. At week 96,ranibizumab PDS reported observed mean BCVA changes from baseline (-1.0; +4.2; ETDRS letters)compared to monthly intravitreal ranibizumab (-1.1; +6.1; ETDRS letters). However, there was anincrease in mean CFT changes from baseline (+9.9; +22.3 vs ?1.3; ?35.8, ?m) and severe adverseevents frequency (22; 4 vs 4; 0) with ranibizumab PDS versus monthly intravitreal ranibizumab,respectively.
 ConclusionRanibizumab PDS showed comparable visual outcomes to intravitreal ranibizumab whiledemonstrating inferior anatomical outcomes and higher incidence of severe adverse effects. Despitethis, with fewer treatment visits required for up to 24 weeks, ranibizumab PDS can potentiallyreduce the treatment burden in nAMD patients with poor compliance. Further studies are needed toprovide better patient eligibility guidelines and recommendations for adverse event management ofranibizumab PDS.

Reducing Treatment Burden for Age-Related Macular Degeneration Patients: A Systematic Review of Ranibizumab Port Delivery System

Introduction & ObjectivesRanibizumab port delivery system (PDS) is a newly developed method that provides a continuous,long-term supply of ranibizumab into the vitreous, reducing the burden of monthly intravitrealinjection visits for neovascular age-related macular degeneration (nAMD) patients. This review aimsto evaluate the efficacy and safety of ranibizumab PDS in nAMD.
 MethodsAn extensive literature search was performed on 4 online databases: PubMed, Cochrane, ProQuest,and ScienceDirect. The inclusion criteria are human studies comparing ranibizumab port deliverysystem and intravitreal ranibizumab, English language, with full-text journal available. The mainoutcome measurements are best-corrected visual acuity (BCVA) in Early Treatment DiabeticRetinopathy Study (ETDRS) letters, central foveal thickness (CFT), and adverse events.
 ResultsTwo randomized controlled trials (RCTs) with a total of 638 adults were evaluated. At week 96,ranibizumab PDS reported observed mean BCVA changes from baseline (-1.0; +4.2; ETDRS letters)compared to monthly intravitreal ranibizumab (-1.1; +6.1; ETDRS letters). However, there was anincrease in mean CFT changes from baseline (+9.9; +22.3 vs ?1.3; ?35.8, ?m) and severe adverseevents frequency (22; 4 vs 4; 0) with ranibizumab PDS versus monthly intravitreal ranibizumab,respectively.
 ConclusionRanibizumab PDS showed comparable visual outcomes to intravitreal ranibizumab whiledemonstrating inferior anatomical outcomes and higher incidence of severe adverse effects. Despitethis, with fewer treatment visits required for up to 24 weeks, ranibizumab PDS can potentiallyreduce the treatment burden in nAMD patients with poor compliance. Further studies are needed toprovide better patient eligibility guidelines and recommendations for adverse event management ofranibizumab PDS.

Short-Term Outcomes of 3 Monthly intravitreal Faricimab On Different Subtypes of Neovascular Age-Related Macular Degeneration.

To evaluate the efficacy and safety of faricimab injections for treatment-naïve neovascular age-related macular degeneration (nvAMD) patients, including subtypes and pachychoroid phenotypes, and identify predictive factors for visual outcomes. nvAMD patients were prospectively recruited, receiving three monthly faricimab (6 mg) injections. Best-corrected visual acuity (BCVA) two months after the last injection (month 4) was compared between subtypes, and between pachychoroid neovasculopathy (PNV) and non-PNV eyes. Regression analysis determined factors influencing month 4 BCVA. The study involved 23 patients (12 typical AMD [tAMD], 10 polypoidal choroidal vasculopathy [PCV], 1 retinal angiomatous proliferation [RAP]). Eleven exhibited PNV phenotype. Significant BCVA (P = 4.9 × 10-4) and central retinal thickness (CRT) (P = 1.3 × 10-5) improvements were observed post-faricimab treatment. The therapy demonstrated favourable results for both tAMD and PCV eyes, and non-PNV and PNV eyes. Faricimab achieved dry macula in 77.3% of eyes, with subretinal fluid resolution in most cases, although intraretinal fluid (IRF) often persisted. Multivariable analysis identified external limiting membrane (ELM) presence and IRF as BCVA contributors at month 4. Faricimab demonstrated significant effectiveness and safety in treatment-naïve nvAMD patients, particularly for PCV and PNV eyes. ELM presence and IRF is predictive of visual outcomes.

Efficacy and safety of intravitreal faricimab for neovascular age-related macular degeneration: a systematic review and meta-analysis

We conducted a systematic review and meta-analysis to evaluate the visual, anatomical, and safety outcomes of the intravitreal faricimab, a novel vascular endothelial growth factor (VEGF)/angiopoietin-2 (Ang-2) bispecific agent, in neovascular age-related macular degeneration (nAMD) patients. The follow-up times in the included studies ranged from a minimum of 36 weeks to a maximum of 52 weeks. EMBASE, Ovid-Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, the WHO ICTRP, ClinicalTrial.gov, the EU Clinical Trials Register, and Chinese Clinical Trial Registry (ChiCTR) were searched (The last literature search was performed on August 17, 2023) for randomized controlled trials (RCTs) comparing faricimab with control groups for neovascular age-related macular degeneration (nAMD). The risk of bias for eligible RCTs was independently assessed using the Cochrane Risk of Bias Tool by two authors (W.-T.Y. and C.-S.W.). The meta-analysis was conducted using Review Manager 5.4 software. The mean best corrected visual acuity (BCVA), central subfield thickness (CST), total choroidal neovascularization (CNV) area, and total lesion leakage were analyzed as continuous variables and the outcome measurements were reported as the weighted mean difference (WMD) with a 95% confidence interval (CI). The ocular adverse events and ocular serious adverse events were analyzed as dichotomous variables and the outcome measurements were analyzed as the odds ratios (ORs) with a 95% CI. Random-effects model was used in our study for all outcome synthesizing due to different clinical characteristics. Four RCTs with 1,486 patients were eligible for quantitative analysis. There was no statistically significant difference between intravitreal faricimab and anti-VEGF in BCVA [weighted mean difference (WMD) = 0.47; 95% CI: (− 0.17, 1.11)]. The intravitreal faricimab group showed numerically lower CST [WMD = − 5.96; 95% CI = (− 7.11, − 4.82)], total CNV area [WMD = − 0.49; 95% CI = (− 0.68, − 0.30)], and total lesion leakage [WMD = − 0.88; 95% CI = (− 1.08, − 0.69)] after intravitreal therapy compared with the intravitreal anti-VEGF group. There were no statistically significant differences between intravitreal faricimab and anti-VEGF in ocular adverse events (AEs) [pooled odds ratio (OR) = 1.10; 95% CI = (0.81, 1.49)] and serious adverse events (SAEs) [pooled OR = 0.84; 95% CI = (0.37, 1.90)]. The intravitreal bispecific anti-VEGF/angiopoietin 2 (Ang2) antibody faricimab with a extended injection interval was non-inferior to first-line anti-VEGF agents in BCVA. It was safe and had better anatomical recovery. Large, well-designed RCTs are needed to explore the potential benefit of extended faricimab for nAMD. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022327450).

Relationships between Patient-Reported Outcome Measures and Clinical Measures in Naïve Neovascular Age-Related Macular Degeneration Patients Treated with Intravitreal Ranibizumab.

Our objective was to evaluate changes in patient-reported outcome measures using the NEI-VFQ 25 questionnaire during a treat and extend regimen in naive neovascular Age-Related Macular Degeneration patients, and its correlation with anatomical and functional data. We conducted a prospective observational study. Patients underwent a treat and extend regimen with intravitreal ranibizumab for neovascular Age-Related Macular Degeneration. Initial response was evaluated at 4th month, and subsequently in every follow-up visit. If a clinical response was achieved, the injection interval was extended in two-week increments, up to a maximum of 12 weeks. Quality of life was assessed using the NEI-VFQ 25 questionnaire at baseline, 4th months, and 12th months. Patients were categorized as good or poor responders based on Best corrected visual acuity, central foveal thickness, intraretinal fluid, or subretinal fluid. Treatment with ranibizumab led to a significant improvement in quality of life, with a mean increase in NEI-VFQ 25 score of 4.27 points in the 12th month. No significant differences in improvement were observed between good and poor responders. Quality of life scores in neovascular Age-Related Macular Degeneration patients improved with intravitreal treatment regardless of the clinical response. The early response following the loading phase could indicate better quality of life after one year of treatment, with Best corrected visual acuity being the clinical parameter with the greatest influence on quality of life.

European Unmet Needs in the Management of Neovascular Age-Related Macular Degeneration in Daily Practice: Data from the Fight Retinal Blindness! Registry

PurposeTo evaluate the proportion, predictors and outcomes of neovascular age-related macular degeneration (nAMD) patients treated with a high burden of vascular endothelial growth factor (VEGF) inhibitor injections (IVT) after two years in routine clinical practice. DesignRetrospective analysis of data from a prospectively designed observational outcomes registry, Fight Retinal Blindness! project, of patients treated in European centers. ParticipantsTreatment-naïve eyes (one eye per patient) starting VEGF inhibitors for nAMD from January 2017 to March 2020 with 24 months of follow-up. We analyzed three treatment burden groups defined by the mean interval of the three closest injections to the 24-month visit: (1) those with a high treatment burden had injection intervals ≤ 42 days, (2) those with a low treatment burden had injection intervals between 43 and 83 days and those with tolerable treatment burden had injection intervals between 84 and 365 days. MethodsMultinomial regression was used to evaluate baseline risk predictors of patients requiring a high treatment burden. Main Outcome MeasuresThe proportion of patients that experienced a high treatment burden at 2 years and its predictors. ResultsWe identified 2,038 eligible patients completing 2 years of treatment (2038/3943 patients [60%]) with a median (Q1, Q3) of 13 (10, 17) injections. The proportion of patients with a high treatment burden was 25% (516 patients) at 2 years. Younger patients (Odds ratio (OR), 0.97; 95%CI, 0.96-0.99; P<0.01) were more likely to have high treatment burden, while eyes with type 3 CNV at baseline were significantly less likely (OR, 0.26; 95%CI, 0.13-0.52; P<0.01). Regarding type of fluid, patients with subretinal fluid only at baseline (OR, 3.85; 95%CI, 1.34-11.01; P=0.01) and persistent active intraretinal (OR, 1.56; 95%CI, 1.18-2.06; P<0.01) or subretinal fluid only (OR, 2.21; 95%CI, 1.52-3.21; P<0.01) after the loading phase had a higher risk of high treatment burden at 2 years. ConclusionsHigh treatment burden is common issue in routine clinical practice in Europe, with a quarter of patients requiring injections of conventional VEGF inhibitors every 6 weeks at 2 years and 40 percent discontinuing treatment within 2 years.

PGC‐1a inhibition promotes autophagy in induced pluripotent stem cell‐derived retinal pigment epithelial cells generated from age‐related macular degeneration patients

Aims/Purpose: Dysfunctional protein clearance, oxidative stress, mitochondrial damage, and chronic inflammation cause retinal pigment epithelial (RPE) cell damage and the development of age‐related macular degeneration (AMD). PGC‐1α can alleviate oxidative stress, is a key player in mitochondrial quality control and could be considered as a treatment target in AMD. Here, we assessed the effect of PGC‐1α inhibition on induced pluripotent stem cell (iPSC)‐derived RPE cells exposed to hydroquinone‐induced oxidative stress.Methods: iPSC‐derived RPE cells from two neovascular AMD patients or one healthy age‐matched control were cultured for 8 weeks on transwell cell culture inserts until mature. Cells were exposed to the PGC‐1α inhibitor SR‐18292 for 1 h before an exposure to hydroquinone for an additional 4 h. Lactate dehydrogenase (LDH) was measured from collected medium samples to assess cellular viability. Cells were lysed in 3x Laemmli sample buffer for analysis by western blotting or subjected to RNA extraction, followed by RT‐PCR analysis.Results: Hydroquinone caused a robust increase in LDH release to the medium, which was not modulated by PGC‐1α inhibition. In neovascular AMD‐derived iPSC‐RPE cells, hydroquinone caused an accumulation of p62 and LC3‐II, an effect that was reversed by SR‐18292 pre‐treatment. In control iPSC‐RPE cells, neither hydroquinone nor SR‐18292 affected autophagic markers p62 or LC3. RT‐PCR analysis showed an increase in p62 mRNA levels following hydroquinone exposure in both control‐ and AMD‐derived iPSC‐RPE cells while no change was observed in the RNA levels of LC3B or mTOR.Conclusions: Increased oxidative stress caused autophagy dysregulation in AMD‐derived iPSC‐RPE cells but not in healthy age‐matched control cells. Interestingly, PGC‐1α inhibition promoted autophagy and the clearance of p62, but further studies are necessary to explore the underlying pathways and the disease‐specific differences observed between healthy and disease‐derived RPE cells.

Choroidal thickness after anti‐vascular endothelial growth factor in treatment‐naïve typical neovascular age‐related macular degeneration patients: A systematic review and meta‐analysis

Aims/Purpose: To evaluate the effect of anti‐vascular endothelial growth factor (anti‐VEGF) on choroidal thickness (CT) in treatment‐naïve typical neovascular age‐related macular degeneration (AMD) patients during the loading phase.Methods: A systematic literature search was conducted in CENTRAL, MEDLINE, EMBASE, Scopus, Web of Science, Clinical Trials, ICTRP and ISRCTN from inception to October 19, 2022. The protocol was registered with PROSPERO (CRD42022371192). We included both retrospective and prospective randomized controlled trials, cohort studies, case control and case series of typical neovascular AMD patients. Studies with polypoidal choroidal vasculopathy or unclear diagnoses and reports in other languages than English were excluded. Risk of bias was assessed using critical appraisal tools provided by Joanna Briggs Institute.Results: 43 studies were included in the review. Meta‐analysis of all studies reporting sufficient data and simultaneously disregarding measurement technique, macular neovascularization (MNV) type and anti‐VEGF type, yielded a significant decrease of CT with anti‐VEGF treatment. To decrease bias, sub‐analyses for Type 1 and 2 MNV sorted by anti‐VEGF type found a significant effect for both aflibercept and ranibizumab, and the effect appears greater in the aflibercept group. For Type 3 MNV, the baseline CT was generally thinner and the decrease more modest.Conclusions: Anti‐VEGF drugs decrease CT in typical neovascular AMD. There is a greater effect of aflibercept compared to ranibizumab. For bevacizumab and brolucizumab there are few studies, but available data show a tendency of greater effect in the latter. There are low numbers of randomized trials on the topic and publication bias might affect the results. More studies randomized to treatment of patients with a thin baseline choroid should be conducted.

Characteristics of Eyes With Neovascular Age-Related Macular Degeneration Requiring Frequent Anti-vascular Endothelial Growth Factor Injections.

Objective In this study, we aimed to determine the characteristics of neovascular age-related macular degeneration (AMD) patients requiring frequent anti-vascular endothelial growth factor (VEGF) therapy. Methods This was a retrospective observational study involving the review of 32 eyes of 31 patients (25 men and six women, mean age: 74.3 years) treated with anti-VEGF injections for less than eight weeks and at least one year of follow-up. The subtype of macular neovascularization (MNV), follow-up duration, number of injections, visual acuity, and exudative changes during the study period were evaluated. Results Twenty-nine eyes (90.6%) had MNV under the retinal pigment epithelium (RPE), including 11 eyes with type 1 MNV and 18 eyes with polypoidal choroidal vasculopathy (PCV). Only three eyes had type 2 MNV (9.4%) above the RPE. The mean follow-up period was 28.7 ± 16.5 months, and the mean number of injections was 21.5 ± 11.8. The mean visual acuity [logarithm of the minimum angle of resolution (logMAR) units] was 0.19 ± 0.23 at the initial visit to our hospital, which decreased non-significantly to 0.24 ± 0.4 at the final visit (p=0.63). The exudation in four eyes (two with type 1 MNV and two with PCV)never resolved. The exudation remained in 27 eyes (84%) even after every four weeks of treatment, and it was present in five eyes (16%) in the treatment interval of eight weeks. Conclusions In the eyes receiving frequent anti-VEGF injections, the sub-RPE MNV might have affected the response to the treatment. Although patients requiring frequent anti-VEGF therapy did not have a significant decrease in their visual acuity, 84% of the eyes had exudations even with monthly injections.

Intravenous 3K3A-Activated Protein C Inhibits Murine Ocular Inflammation and Suppresses Ocular Choroidal Neovascularization

Introduction: Choroidal neovascularization (CNV) is characterized by the growth of newly formed abnormal blood vessels from the choroid extending into the neurosensory retina, leading to vision loss. CNV is a common cause of visual impairment in neovascular age-related macular degeneration (nAMD) patients. Current treatments failed to stop the continuity of the neurodegenerative process. Despite the urgency, no neuroprotective agent has been found yet to treat AMD and other neurodegenerative ocular diseases. 3K3A-activated protein C (APC) is a cell-signaling analog of the endogenous blood serine protease APC. Preclinical studies showed that circulating plasma 3K3A-APC readily crosses the blood-brain barrier (BBB) and reaches neurons due to EPCR-dependent transport. In rodent models of stroke, brain injury, and neurodegenerative disorders, 3K3A-APC exerts neuroprotective, anti-inflammatory, and vasculoprotective activities. Due to its pleiotropic effects, 3K3A-APC has advanced to clinical trial stages for treating acute brain damage and chronic neurodegenerative diseases, which share similarities with retinal neurodegenerative disorders. Notably, the retina is part of the central nervous system (CNS), and the blood-retina barrier shares functional and structural similarities with the BBB. We previously demonstrated that intraocular administration of 3K3A-APC functions as a pleiotropic cytoprotective molecule within the retina, reducing ocular inflammation, suppressing CNV growth, and exhibiting promising therapeutic potential as a neuroprotective agent for treating ocular disorders. Intraocular administration is commonly utilized for delivering therapeutics to treat retinal conditions. However, safety concerns, the burden on the healthcare system, and patient comfort may indicate that systemic administration of 3K3A-APC is a beneficial alternative. Aim: To determine whether intravenously injecting 3K3A-APC into mice tails will cross the blood-retina barrier, induce anti-inflammatory activities in the retina, and suppress CNV. Methods: The efficacy of systemic administration of 3K3A-APC was evaluated using two C57BL/6J murine models: the LPS-induced ocular inflammation and the laser-induced CNV model. CNV was triggered by laser and ocular inflammation was triggered by intravitreal injection of lipopolysaccharide (LPS). Murine recombinant 3K3A-APC was administered systemically via tail injection. Fluorescein isothiocyanate (FITC)-dextran perfusion followed by retinal flatmount staining with anti-CD11b was used to assess inflammatory co-localization of cells to retinal vessels. FITC-dextran perfusion followed by retinal pigment epithelium (RPE)-choroid flatmount was used to assess CNV vascular penetration using 3D confocal imaging. Results: LPS injection triggered robust inflammatory cell infiltration in both the anterior and posterior chambers of the eyes. Systemic administration of 3K3A-APC (0.5 mg/kg, 1 and 4 hours post-LPS) significantly inhibited ocular inflammation. Immunostaining performed 24 hours post LPS revealed that 3K3A-APC reduced the number of CD11b+ monocyte and their extravasation into the retinal parenchyma (Figure). In the laser-induced CNV model, systemic administration of 0.2 mg/kg 3K3A-APC was applied one hour and four days post-laser. Evaluation of retinal specimens ten days post-laser showed that 3K3A-APC treatment significantly suppressed CNV growth, attenuated the abnormal growth of blood vessels from the choroid into the sensory retina, and decreased myeloid cell recruitment to the RPE-choroid area. Conclusion: Our study reveals that systemically administered 3K3A-APC effectively inhibits ocular inflammation and reduces CNV formation. Drawing insights from the neuroprotective activities of 3K3A-APC in the brain and CNS and recognizing the retina, particularly the macula, as an extension of the brain, we propose 3K3A-APC as a potential neuroprotective treatment for AMD and other neurodegenerative retinal pathologies. Given the established safety of systemic 3K3A-APC administration in phase 2 clinical trials for ischemic stroke, our findings support further exploring 3K3A-APC as a novel therapeutic approach in ophthalmology. Further research is warranted to elucidate fully the mechanisms underlying 3K3A-APC's beneficial effects on the retina.

Predicting Visual Acuity Responses to Anti-VEGF Treatment in the Comparison of Age-related Macular Degeneration Treatments Trials Using Machine Learning

To evaluate multiple machine learning (ML) models for predicting 2-year visual acuity (VA) responses to anti-vascular endothelial growth factor (anti-VEGF) treatment in the Comparison of Age-related Macular Degeneration (AMD) Treatments Trials (CATT) for patients with neovascular AMD (nAMD). Secondary analysis of public data from a randomized clinical trial. A total of 1029 CATT participants who completed 2 years of follow-up with untreated active nAMD and baseline VA between 20/25 and 20/320 in the study eye. Five ML models (support vector machine, random forest, extreme gradient boosting, multilayer perceptron neural network, and lasso) were applied to clinical and image data from baseline and weeks 4, 8, and 12 for predicting 4 VA outcomes (≥ 15-letter VA gain, ≥ 15-letter VA loss, VA change from baseline, and actual VA) at 2 years. The CATT data from 1029 participants were randomly split for training (n= 717), from which the models were trained using 10-fold cross-validation, and for final validation on a test data set (n= 312). Performances of ML models were assessed by R2 and mean absolute error (MAE) for predicting VA change from baseline and actual VA at 2 years, by the area under the receiver operating characteristic curve (AUC) for predicting ≥ 15-letter VA gain and loss from baseline. Using training data up to week 12, the ML models from cross-validation achieved mean R2 of 0.24 to 0.29 (MAE= 9.1-9.8 letters) for predicting VA change and 0.37 to 0.41 (MAE= 9.3-10.2 letters) for predicting actual VA at 2 years. The mean AUCs for predicting ≥ 15-letter VA gain and loss at 2 years was 0.84 to 0.85 and 0.58 to 0.73, respectively. In final validation on the test data set up to week 12, the models had an R2 of 0.33 to 0.38 (MAE= 8.9-9.9 letters) for predicting VA change, an R2 of 0.37 to 0.45 (MAE= 8.8-10.2 letters) for predicting actual VA at 2 years, and AUCs of 0.85 to 0.87 and 0.67 to 0.79 for predicting ≥ 15-letter VA gain and loss, respectively. Machine learning models have the potential to predict 2-year VA response to anti-VEGF treatment using clinical and imaging features from the loading dose phase, which can aid in decision-making around treatment protocols for patients with nAMD. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

MULTIMODAL IMAGING IN NONEXUDATIVE CHOROIDAL NEOVASCULARIZATION: A Pilot Study of Status of Retinal Pigment Epithelium.

To study the status of retinal pigment epithelium in nonexudative and active choroidal neovascularization (CNV) in neovascular age-related macular degeneration. Only treatment-naïve neovascular age-related macular degeneration patients were enrolled in this prospective case-control study, including 17 eyes with nonexudative CNV (6 males and 11 females, 74.9 ± 10.0 years) and 28 eyes with active CNV (8 males and 20 females, 69.3 ± 6.8 years). All patients received a comprehensive ophthalmic examination, optical coherence tomography, dark-field scanning laser ophthalmoscopy, and fundus autofluorescence. The status of the retinal pigment epithelium was assessed with ImageJ software as the brightness of the CNV region on transillumination optical coherence tomography, dark-field scanning laser ophthalmoscopy, and fundus autofluorescence images. Choroidal neovascularization vessel density was measured based on optical coherence tomography angiography. The brightness of CNV region in nonexudative CNV was statistically significantly lower than in active CNV with both optical coherence tomography transillumination ( P = 0.004) and dark-field scanning laser ophthalmoscopy ( P = 0.0015). No difference in brightness of the CNV region between nonexudative and active CNV was found based on fundus autofluorescence ( P = 0.44). The vessel density of nonexudative CNV was statistically significantly higher than that of active CNV with a median value of 64.5% (95% confidential interval [CI] 53.4-79.0%) and 55.3% (95% CI 52.2-60.0%), respectively ( P = 0.05). Multimodal imaging revealed substantial alteration of the retinal pigment epithelium in active CNV but not in nonexudative CNV which correlates with the higher vessel density of nonexudative CNV.