Treatment Of Wet Age-related Macular Degeneration Research Articles

Different Therapeutic Approaches for Dry and Wet AMD.

Age-related macular degeneration (AMD) is the most common cause of irreversible loss of central vision in elderly subjects, affecting men and women equally. It is a degenerative pathology that causes progressive damage to the macula, the central and most vital part of the retina. There are two forms of AMD depending on how the macula is damaged, dry AMD and wet or neovascular AMD. Dry AMD is the most common form; waste materials accumulate under the retina as old cells die, not being replaced. Wet AMD is less common, but can lead to vision loss much more quickly. Wet AMD is characterized by new abnormal blood vessels developing under the macula, where they do not normally grow. This frequently occurs in patients who already have dry AMD, as new blood vessels are developed to try to solve the problem. It is not known what causes AMD to develop; however, certain risk factors (i.e., age, smoking, genetic factors) can increase the risk of developing AMD. There are currently no treatments for dry AMD. There is evidence that not smoking, exercising regularly, eating nutritious food, and taking certain supplements can reduce the risk of acquiring AMD or slow its development. The main treatment for wet AMD is inhibitors of VEGF (vascular endothelial growth factor), a protein that stimulates the growth of new blood vessels. VEGF inhibitors can stop the growth of new blood vessels, preventing further damage to the macula and vision loss. In most patients, VEGF inhibitors can improve vision if macular degeneration is diagnosed early and treated accordingly. However, VEGF inhibitors cannot repair damage that has already occurred. Current AMD research is trying to find treatments for dry AMD and other options for wet AMD. This review provides a summary of the current evidence regarding the different treatments aimed at both forms of AMD with particular and greater attention to the dry form.

Computer Modeling of Bevacizumab Drug Distribution After Intravitreal Injection in Rabbit and Human Eyes.

Age-related macular degeneration (AMD) is a progressive eye disease that causes loss of central vision and has no cure. Wet AMD is the late neovascular form treated with vascular endothelial growth factor (VEGF) inhibitors. VEGF is the critical driver of wet AMD. One common off-label anti-VEGF drug used in AMD treatment is bevacizumab. Experimental efforts have been made to investigate the pharmacokinetic (PK) behavior of bevacizumab in vitreous and aqueous humor. Still, the quantitative effect of elimination routes and drug concentration in the macula are not well understood. In this work, we developed two spatial models representing rabbit and human vitreous to better understand the PK behavior of bevacizumab. This study explores different cases of drug elimination and the effects of injection location on drug concentration profiles. The models are validated by comparing them with experimental data. Our results suggest that anterior elimination is dominant for bevacizumab clearance from rabbit vitreous, whereas both anterior and posterior elimination have similar importance in drug clearance from the human vitreous. Furthermore, results indicate that drug injections closer to the posterior segment of the vitreous help maintain relevant drug concentrations for longer, improving bevacizumab duration of action in the vitreous. The rabbit and human models predict bevacizumab concentration in the vitreous and fovea, enhancing knowledge and understanding of wet AMD treatment.

A Review of Age-related Macular Degeneration and Current Concepts in Management

Abstract Age-related macular degeneration (AMD) is a prevalent and progressive retinal disease that affects a substantial number of elderly individuals worldwide. This manuscript provides a comprehensive overview of the current concepts in the management of AMD. The abstract begins with a brief description of the epidemiology and risk factors associated with AMD, emphasizing its increasing prevalence due to population aging. The two main subtypes of AMD, namely dry and wet, are discussed in detail, highlighting their clinical features, pathophysiology, and diagnostic techniques. The manuscript then focuses on the current management strategies for AMD. It emphasizes the significance of lifestyle modifications, including smoking cessation, healthy diet, and regular exercise, in reducing the risk and progression of AMD. Pharmacological interventions, particularly anti-vascular endothelial growth factor (anti-VEGF) agents, are extensively reviewed as the mainstay of treatment for wet AMD. The potential of emerging therapies and combination treatments is also explored. Furthermore, the manuscript addresses the role of nutritional supplements and antioxidant therapies in the management of dry AMD. It also discusses the importance of early detection and monitoring, highlighting the role of innovative imaging technologies and genetic testing in personalized treatment approaches. In conclusion, this manuscript provides a comprehensive overview of the current management strategies for AMD. By summarizing the latest advances in both pharmacological and non-pharmacological interventions, it serves as a valuable resource for clinicians, researchers, and healthcare professionals involved in the care of AMD patients. The insights presented in this manuscript contribute to the development of effective approaches in the early detection, prevention, and treatment of this visually devastating condition.

Multifunctional Nanotherapeutics with Long-Acting Release against Macular Degeneration by Minimally Invasive Administration.

Neovascular age-related macular degeneration (AMD), a leading cause of blindness, requires frequent intravitreal injection of antivascular endothelial growth factor (anti-VEGF), which could generate a succession of complications with poor patient compliance. The current VEGF-targeting therapies often fail in half of patients due to the complex pathologic microenvironment of excessive reactive oxygen species (ROS) production, and increased levels of inflammation are accompanied by choroidal neovascularization (CNV). We herein reported multifunctional nanotherapeutics featuring superior antioxidant and anti-inflammation properties that aim to reverse the pathological condition, alongside its strong targeted antiangiogenesis to CNV and its ability to provide long-term sustained bioactive delivery via the minimally invasive subconjunctival injection, so as to achieve satisfactory wet AMD treatment effects. Concretely, the nanomedicine was designed by coencapsulation of astaxanthin (AST), a red pigmented carotenoid known for its antioxidative, anti-inflammatory and antiapoptotic properties, and axitinib (AXI), a small molecule tyrosine kinase inhibitor that selectively targets the vascular epidermal growth factor receptor for antiangiogenesis, into the Food and Drug Administration (FDA) approved poly(lactic-co-glycolic acid) (PLGA), which forms the nanodrug of PLGA@AST/AXI. Our results demonstrated that a single-dose subconjunctival administration of PLGA@AST/AXI showed a rational synergistic effect by targeting various prevailing risk factors associated with wet AMD, ensuring persistent drug release profiles, maintaining good ocular biocompatibility, and causing no obvious mechanical damage. Such attributes are vital and hold significant potential in treating ocular posterior segment diseases. Moreover, this nanotherapeutic strategy represents a versatile and broad-spectrum nanoplatform, offering a promising alternative for the complex pathological progression of other neovascular diseases.

Challenges and opportunities of developing small-molecule therapies for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of vision loss in senior adults. The disease can be categorized into two types: wet AMD and dry AMD. Wet AMD, also known as exudative or neovascular AMD, is less common but more severe than dry AMD and is responsible for 90% of the visual impairment caused by AMD and affects 20 million people worldwide. Current treatment options mainly involve biologics that inhibit the vascular endothelial growth factor or complement pathways. However, these treatments have limitations such as high cost, injection-related risks, and limited efficacy. Therefore, new therapeutic targets and strategies have been explored to improve the outcomes of patients with AMD. A promising approach is the use of small-molecule drugs that modulate different factors involved in AMD pathogenesis, such as tyrosine kinases and integrins. Small-molecule drugs offer advantages, such as oral administration, low cost, good penetration, and increased specificity for the treatment of wet and dry AMD. This review summarizes the current status and prospects of small-molecule drugs for the treatment of wet AMD. These advances are expected to support the development of effective and targeted treatments for patients with AMD.

Novel therapeutic perspectives for wet age-related macular degeneration: RGD-modified liposomes loaded with 2-deoxy-D-glucose as a promising nanomedicine

Choroidal neovascularization (CNV), characterized as a prominent feature of wet age-related macular degeneration (AMD), is a primary contributor to visual impairment and severe vision loss globally, while the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells is dictated by angiogenic growth factors alone. Even though treatments targeting vascular endothelial growth factor (VEGF), like Ranibizumab, are widely administered, more than half of the patients still exhibit inadequate or null responses, emphasizing the imperative need for solutions to this problem. Here, aiming to explore therapeutic strategies from a novel perspective of endothelial cell metabolism, a biocompatible nanomedicine delivery system is constructed by loading RGD peptide-modified liposomes with 2-deoxy-D-glucose (RGD@LP-2-DG). RGD@LP-2-DG displayed good targeting performance towards endothelial cells and excellent in vitro and in vivo inhibitory effects on neovascularization were demonstrated. Moreover, our mechanistic studies revealed that 2-DG interfered with N-glycosylation, leading to the inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream signaling. Notably, the remarkable inhibitory effect on neovascularization and biocompatibility of RGD@LP-2-DG render it a highly promising and clinically translatable therapeutic candidate for the treatment of wet AMD and other angiogenic diseases, particularly in patients who are unresponsive to currently available treatments.

MicroRNA expression profiling in tears and blood as predictive biomarkers for anti-VEGF treatment response in wet age-related macular degeneration.

This study aimed to investigate the potential of microRNAs (miRNAs) in tears, blood, and aqueous humor as biomarkers for predicting treatment response in wet age-related macular degeneration (AMD) patients undergoing anti-vascular endothelial growth factor (anti-VEGF) therapy. In a single-center prospective cohort study, treatment-naïve wet AMD patients and age-matched controls were enrolled. Clinical data and miRNA levels (miR-199a-3p, miR-365-3p, miR-200b-3p, miR-195-5p, miR-335-5p, and miR-185-5p) in tears, blood, and aqueous humor were collected. Treatment response was categorized into responders and non-responders based on visual acuity and central subfield thickness. MiRNA levels were quantified using reverse-transcription PCR. Statistical analyses were performed, including ROC analysis, to evaluate predictive accuracy. Dysregulated miRNA profiles were observed in wet AMD tears and blood compared to controls. Specifically, miR-199a-3p, miR-195-5p, and miR-185-5p were upregulated, while miR-200b-3p was downregulated in tears. All six miRNAs were elevated in wet AMD blood samples. Notably, responders showed higher tear expression of miR-195-5p and miR-185-5p. Combining these miRNAs yielded the highest predictive power (AUC = 0.878, p = 0.006) for anti-VEGF responders. Dysregulated miRNA profiles in tears and blood suggest their potential as biomarkers for wet AMD. MiR-195-5p and miR-185-5p in tears demonstrate predictive value for anti-VEGF treatment responders. This study underscores the non-invasive prediction potential of miRNA tear analysis in wet AMD treatment responses.

Analysis of the Molecular Mechanism of Xueshuantong in the Treatment of Wet Age-Related Macular Degeneration (AMD) Using GEO Datasets, Network Pharmacology, and Molecular Docking.

At present, the main treatment method for wet AMD is single anti-VEGF therapy, which can require multiple injections, is costly and may have poor efficacy. Studies and clinical experiments have shown that the oral Chinese medicine Xueshuantong combined with anti-VEGF therapy is more effective, and this study aims to explore the molecular mechanism. The TCMSP database was used to identify the main Xueshuantong components. The PubChem database and SWISS Target Prediction data were used to find the SMILES molecular formulas of compounds and corresponding target genes and disease-related genes were searched using the GEO, DisGeNET, and GeneCards databases. Venny was used to identify the intersecting wet AMD-related genes and Xueshuantong targets and Cytoscape software was used to construct direct links between the drug components and disease targets. Then, PPI networks were constructed using the STRING website. R software was used for GO and KEGG enrichment analyses. Cytoscape software was used for topological analyses, and AutoDock Vina v.1.1.2 software was used for molecular docking. 64 compounds corresponding to four drugs were found by the TCMSP database, 1001 total drug targets were found by the PubChem database, 607 wet AMD target genes were found by the GEO, DisGeNET, and GeneCards databases, and 87 Xueshuantong target genes for wet AMD were obtained. Then, by constructing the drug component and disease target network and PPI network, we found that the components closely interacted with VEGF, TNF, caspase 3, CXCL8, and AKT1, which suggested that the therapeutic effects might be related to the inhibition of neovascularization, inflammation, and AKT pathway. Then, GO enrichment analysis showed that the biological processes response to hypoxia, positive regulation of angiogenesis, and inflammatory response were enriched. KEGG enrichment results showed that the HIF-1 and pi3k-akt pathways may mediate the inhibition of wet AMD by Xueshuantong. Topological analysis results identified 10 key proteins, including VEGF, TNF, AKT1, and TLR4. The results of molecular docking also confirmed their strong binding to their respective compounds. In this study, it was confirmed that Xueshuantong could inhibit wet AMD by targeting VEGF, TNF, TLR4, and AKT1, multichannel HIF-1, and the PI3K-AKT pathway, which further proved the therapeutic effects of Xueshuantong combined with single anti-VEGF therapy on wet AMD and provided new insights into the study of novel molecular drug targets for the treatment of wet AMD.

A New Generation of Gene Therapies as the Future of Wet AMD Treatment.

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms, dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the concept of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the progress to the clinic of "one and done" therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management.

Topical Application of Cell-Penetrating Peptide Modified Anti-VEGF Drug Alleviated Choroidal Neovascularization in Mice.

Age-related macular degeneration (AMD) stands as the foremost cause of irreversible central vision impairment, marked by choroidal neovascularization (CNV). The prevailing clinical approach to AMD treatment relies on intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs. However, this method is encumbered by diverse complications, prompting exploration of non-invasive alternatives such as ocular administration via eye drops for anti-VEGF therapy. Two complexes, 5-FITC-CPP-Ranibizumab (5-FCR) and 5-FITC-CPP-Conbercept (5-FCC), were synthesized by incorporating the anti-VEGF drugs Ranibizumab (RBZ) or Conbercept (CBC) with cell-penetrating peptide (CPP). Circular dichroism spectrum (CD) facilitated complexes characterization. Eye drops was utilized to address laser-induced CNV in mice. Fluorescein fundus angiography (FFA) observe the CNV lesion, while FITC-dextran and IB4 dual fluorescent staining, along with hematoxylin-eosin (HE) staining, assessed in lesion size. Tissue immunofluorescence examined CD31 and VEGF expression in choroidal/retinal pigment epithelial (RPE) tissues. Biocompatibility and biosafety of 5-FCR and 5-FCC was evaluated through histological examination of various organs or cell experiments. Both 5-FCR and 5-FCC exhibited favorable biocompatibility and safety profiles. VEGF-induced migration of Human umbilical vein endothelial cells (HUVECs) significantly decreased post-5-FCR/5-FCC treatment. Additionally, both complexes suppressed VEGF-induced tube formation in HUVECs. FFA results revealed a significant improvement in retinal exudation in mice. Histological examination unveiled the lesion areas in the 5-FCR and 5-FCC groups showed a significant reduction compared to the control group. Similar outcomes were observed in histological sections of the RPE-choroid-sclera flat mounts. In this study, utilizing the properties of CPP and two anti-VEGF drugs, we successfully synthesized two complexes, 5-FCR and 5-FCC, through a straightforward approach. Effectively delivering the anti-VEGF drugs to the target area in a non-invasive manner, suppressing the progression of laser-induced CNV. This offers a novel approach for the treatment of wet AMD.

Association between Oral Active-Matrix Metalloproteinase-8 Levels and Subretinal Fibrosis among Wet Age-Related Macular Degeneration Patients

Purpose Periodontitis causes low-grade systemic inflammation and has been associated with elevated active-matrix metalloproteinase (aMMP-8) levels, blood-ocular barrier breakdown and a risk of wet age-related macular degeneration. To assess the association between aMMP-8 levels and macular status among patients with wet age-related macular degeneration (AMD). Methods Patients on anti-VEGF treatment for wet AMD were enrolled for oral aMMP-8 rinse test in Mehiläinen Private Hospital, Helsinki, Finland. Macular status was examined from spectral-domain optical coherence tomography (SD-OCT) scans by a medical retina specialist and aMMP-8 levels were analyzed with chairside point-of-care oral rinse (PerioSafe®) test and real-time quantitated by a dentist using the ORALyzer®- reader with a 10 ng/ml cut-off for aMMP-8 activity. Results Elevated aMMP-8 levels were found in 10 out of 32 patients. Age, gender, anti-VEGF (bevacizumab or aflibercept) distribution, cumulative number of anti-VEGF injections and treatment interval were comparable between patients with aMMP-8 levels below and above the point-of-care level. Macular status differed in regard to aMMP-8 activity; among patients with aMMP-8 levels below the point-of-care subretinal fibrosis was found in 6 out of 22 eyes, whereas among patients with aMMP-8 levels above the point-of-care subretinal fibrosis was found in 8 out of 10 eyes (p = 0.005). Respectively, the mean thickness of subretinal fibrosis at fovea was 19.5 ± 44.1 and 92.3 ± 78.3 µm (p = 0.018). No differences were found in the presence and in the area of geographic atrophy, or fluid distribution, whereas thicknesses of serous pigment epithelial detachment (65.5 ± 99.5 and 12.9 ± 27.9 µm, p = 0.038) and neuroretina (204.2 ± 57.8 µm and 143.0 ± 43.7 µm, p = 0.006) were greater in the eyes of patients with physiological aMMP-8 levels compared to those with elevated aMMP-8 levels. Conclusion Elevated aMMP-8 levels may account for subretinal fibrosis formation in wet AMD.

Anti-Vascular Endothelial Growth Factor Drugs for Age-Related Macular Degeneration

What Is the Issue?
 
 Wet age-related macular degeneration (AMD) is a serious health concern that causes reduced vision-related function, poor overall quality of life, and increased health care resource usage.
 Anti-vascular endothelial growth factor (VEGF) drugs are the first-line treatment for wet AMD, and they are injected into the eye. These drugs can slow disease progression but are expensive and require trained medical professionals to administer and monitor treatment response.
 The criteria for initial injection, maintenance, and discontinuation of anti-VEGF drugs in patients with wet AMD remain unclear.
 
 What Did We Do?
 
 To inform decisions about the appropriate use of anti-VEGF drugs to treat adults with wet AMD, CADTH sought to identify and summarize recommendations about criteria for the diagnosis of wet AMD and best practices for subsequent treatment with anti-VEGF drugs.
 An information specialist searched the peer-reviewed and grey literature for clinical practice guidelines published since 2018.
 
 What Did We Find?
 
 Three evidence-based guidelines recommend optical coherence tomography (OCT) to assess patients with suspected wet AMD. The National Institute for Health and Care Excellence (NICE) guidelines then strongly recommend fundus fluorescein angiography only when OCT does not exclude neovascular disease.
 The evidence-based guidelines recommend anti-VEGF drugs for wet or neovascular AMD in adults, particularly for patients with recent disease progression. One guideline suggests starting anti-VEGF treatment as soon as possible once the diagnosis of wet AMD is made.
 The NICE guideline suggests that there may not be any clinically significant distinctions in the effectiveness and safety of various anti-VEGF treatments, including aflibercept, bevacizumab, and ranibizumab, indicating a need for an individualized approach when selecting specific anti-VEGF drugs. However, 1 guideline is inconsistent with NICE, as it suggests choosing bevacizumab first.
 During the maintenance phase of using anti-VEGF drugs, it is important to closely monitor the patient's response and the disease activity and adjust the injection intervals accordingly.
 Guidelines recommend taking an individualized approach and emphasizing active patient involvement in switching and discontinuing anti-VEGF drugs for adults with wet AMD.
 Guidelines or guidance documents without a literature search or unclear methods provided generally consistent recommendations with the included evidence-based guidelines.
 We did not identify any evidence-based guidelines regarding the use of faricimab or brolucizumab. However, NICE published technology appraisals supporting the use of recently approved anti-VEGF drugs (faricimab and brolucizumab) as alternative options for patients who meet similar criteria for treatment with bevacizumab or aflibercept, and under agreed pricing conditions.
 
 What Does It Mean?
 
 All identified guidelines consistently recommend anti-VEGF drugs for adults with wet active AMD, with some providing guidance on the use of OCT and other ophthalmological assessments to identify criteria for starting and adjusting treatment.
 These guidelines recommend personalized and patient-centred approaches for selecting, switching, and discontinuing anti-VEGF medications. Cost is also a crucial factor in decision-making, especially for aflibercept, ranibizumab, and recently approved anti-VEGF drugs such as faricimab and brolucizumab.
 Further research and evidence-based guidelines are necessary to confirm whether newer drugs can be used in similar situations as older drugs.

End binding-3 inhibitor activates regenerative program in age-related macular degeneration

Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is a need for the development of less invasive treatments. Here, we designed an allosteric inhibitor of end binding-3 (EB3) protein, termed EBIN, which reduces the effects of environmental stresses on endothelial cells by limiting pathological calcium signaling. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of wet AMD prevents both neovascular leakage and choroidal neovascularization. EBIN reverses the epigenetic changes induced by environmental stresses, allowing an activation of a regenerative program within metabolic-active endothelial cells comprising choroidal neovascularization (CNV) lesions. These results suggest the therapeutic potential of EBIN in preventing the degenerative processes underlying wet AMD.

Efficacy οf Wet Age-related Macular Degeneration Treatment οn Reading: A Pilot Study Using Eye-movement Analysis.

Functional vision, as evaluated with silent passage reading speed, improves after anti-vascular endothelial growth factor (anti-VEGF) treatment in patients with wet age-related macular antidegeneration (wAMD), reflecting primarily a concomitant reduction in the number of fixations. Implementing eye movement analysis when reading may better characterize the effectiveness of therapeutic approaches in wAMD. This study aimed to evaluate silent reading performance by means of eye fixation analysis before and after anti-VEGF treatment in wAMD patients. Sixteen wAMD patients who underwent anti-VEGF treatment in one eye and visual acuity (VA) better than 0.5 logMAR served as the AMD group. Twenty adults without ocular pathology served as the control group. Central retinal thickness and near VA were assessed at baseline and 3 to 4 months after their first visit. Reading performance was evaluated using short passages of 0.4-logMAR print size. Eye movements were recorded using EyeLink II video eye tracker. Data analysis included computation of reading speed, fixation duration, number of fixations, and percentage of regressions. Frequency distributions of fixation durations were analyzed with ex-Gaussian fittings. In the AMD group, silent reading speed in the treated eye correlated well with central retinal thickness reduction and improved significantly by an average of 15.9 ± 28.5 words per minute (P = .04). This improvement was accompanied by an average reduction of 0.24 ± 0.38 in fixations per word (P = .03). The corresponding improvement in monocular VA was not statistically significant. Other eye fixation parameters did not change significantly after treatment. No statistically significant differences were found in the control group. Visual acuity tests may underestimate the potential therapeutic effects after anti-VEGF treatment in patients with relatively good acuity who are being treated for wAMD. Evaluating silent reading performance and eye fixation parameters may better characterize the effectiveness of therapeutic approaches in wAMD patients.

GPx4 reduces laser‐induced choroidal neovascularization by inhibiting ferroptosis

AbstractPurpose: To investigate the protective effects of glutathione peroxidase 4 (GPx4) in laser‐Induced age‐related macular degeneration (AMD) animal model.Methods: In this study, Norway brown rats were used to establish a laser‐induced AMD model. To investigate the protective role of GPx4, rats received laser photocoagulation and intravitreal injection of GPx4 (25 μg/eye) or PBS on the same day. The size and vascular leakage of choroidal neovascularization (CNV) were measured on 7 and 14 days after lasing by using OCT and FA. Immunohistochemical staining of the choroidal flat mounts with CD31 were used to assess angiogenesis.Results: Compared with PBS group, intravitreal injection of GPx4 decreased the CNV size of 0.083 ± 0.121, P = 0.07 on day 7 and 0.11 ± 0.135 (p < 0.05) on day 14. By leakage grading, the CNV lesion with pathologically significant leakage (grade 2a and 2b) was reduced in GPx4 group (2%) and increased in PBS group (25.6%) from day 7 to day 14. The immunostaining with CD31 showed smaller lesions in GPx4 group than PBS group.Conclusions: This study showed that GPx4 inhibited CNV formation and providing a novel molecular target against ferroptosis for wet AMD treatment.

National clinical guidelines and treatment centralization do not guarantee consistency in healthcare delivery. A mixed-methods study of wet age-related macular degeneration treatment in Denmark

As clinical practice variation has been problematized as a symptom of suboptimal care and inefficient resource spending, consistency in the delivery of healthcare is a recurring policy goal. We examine a case where the introduction of a new treatment is most likely to provide consistency in healthcare delivery because it was introduced with a national clinical practice guideline representing consensus about best clinical practice among leading clinicians, and because care delivery was highly centralized to few high-volume treatment units. Despite the consensus on best clinical practice and care centralization, this study shows pronounced regional variation in patient outcomes and treatment costs that increased over time. Using a mixed-methods design, we find that the lack of consistency in care was largely unrelated to patient-specific characteristics, but seemed to reflect structural differences in the regional organization and financing of healthcare delivery. We conclude that the value of clinical practice guidelines is undermined when structural barriers limit the ability of clinicians and clinical managers to scale up treatment, and that some degree of decentralization may be a tool to maintain treatment intensity when the treatment effect is dependent on a high treatment intensity.

Long-Term Visual Outcomes in Exudative Age-Related Macular Degeneration Patients With Unanticipated Gaps in Therapy.

This study's objective was to describe long-term visual outcomes of patients with age-related macular degeneration (AMD) treated with intravitreal anti-vascular endothelial growth factor injections who were lost to follow-up and then resumed treatment with anti-vascular endothelial growth factor injections. This was a retrospective cohort study of eyes with at least 7 years of follow-up following the initiation of treatment for wet AMD with and without gaps in therapy. The baseline mean logMAR visual acuity was 0.65 ± 0.5 (Snellen acuity 20/89) in eyes with gaps in therapy and 0.53 ± 0.3 (20/68) in eyes without gaps. In the initial 7-year follow-up period, the eyes with gaps in therapy had significantly worse visual acuity (P < .001) and this remained significant when accounting for baseline visual acuity (P < .001). Gaps in intravitreal injection therapy for exudative AMD were negatively associated with visual acuity. Adherence to therapy is important to address in the care of patients with exudative AMD. [Ophthalmic Surg Lasers Imaging Retina 2022;53:481-489.].

Antioxidant Properties of Cerium Oxide Nanoparticles Prevent Retinal Neovascular Alterations In Vitro and In Vivo.

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.

Cost Analysis: Port Delivery System versus Monthly Ranibizumab for Wet Age-Related Macular Degeneration Treatment

A cost analysis of the Port Delivery System (PDS) versus monthly intravitreal ranibizumab (IVR) in the treatment of neovascular age-related macular degeneration (AMD) was performed based on the 96-week ARCHWAY trial results.

Smart AMD prognosis through cellphone: an innovative localized AI-based prediction system for anti-VEGF treatment prognosis in nonagenarians and centenarians.

Age-related macular degeneration (AMD) is one of the most common reasons for blindness in the world today. The most common treatment for wet AMD is the intravitreal injections for inhibiting vascular-endothelial-derived growth factor (VEGF). This treatment usually involves multiple injections and thus multiple clinic visits, which not only causes increased cost on national health services but also causes exposure to the hospital environment, which is sometimes high risk considering current COVID crisis. The treatment, in spite of the above concerns, is usually effective. However, in some cases, either the medicine fails to produce the anticipated favourable outcome, resulting in waste of time, medication, efforts, and above all, psychological distress to the patients. Hence, early predictability of anatomical as well as functional effectiveness of the treatment appears to be a very desirable capability to have. A machine learning approach using adaptive neuro-fuzzy inference system (ANFIS) of two-sample prediction model has been presented that requires only the baseline measurements and changes in visual acuity (VA) as well as macular thickness (MAC) after four months of treatment to estimate the values of VA and MAC at 8 and 12months. In contrast to most of the AI techniques, ANFIS approach has shown the capability of the algorithm to work with very small dataset as well, which makes it a perfect candidate for the presented solution. The presented model has shown to have a very high accuracy (> 92%) and works in near-real-time scenarios. It has been converted into a smart phone App, OphnosisAMD, for convenient usage. With this App, the clinician can visualize the progression of the patient for a specific treatment and can decide on continuing or changing the treatment accordingly. The complete AI engine developed with the ANFIS algorithm is localized to the phone through the App, implying that there is no need for internet or cloud connectivity for this App to function. This makes it ideal for remote usage, especially under the current COVID scenarios. With a smart AI-based App on their fingertips, the presented system provides ample opportunity to the doctors to make a better decision based on the estimated progression, if the same drug is continued with (good/fair prognosis) or alternate treatment should be sought (bad prognosis). From a functional point of view, a prediction algorithm is triggered through simple entry of the relevant parameters (baseline and 4months only). No internet/cloud connectivity is needed since the algorithm and the trained network are fully embedded in the App locally. Hence, using the App in remote and/or non-connected isolated areas is possible, especially in the secluded patients during the COVID scenarios.