Retinal pigment epithelium-specific ablation of GPx4 in adult mice recapitulates key features of geographic atrophy in age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly population, particularly the late-stage of dry AMD known as geographic atrophy (GA), lacks effective treatment options. Genetic mouse models of AMD have revealed the significance of impaired lipid metabolism and anti-oxidative capacity in early/intermediate stage of AMD, but remains unclear in GA that severely damages visual function. Here, to investigate the potential relevance of peroxidized lipids in RPE for late-stage dry AMD, GPx4fl/fl mice underwent subretinal injections of RPE-specific AAV-Cre vector or control AAV vector. RPE-specific GPx4 deficiency led to rapid RPE degeneration resembling key features of late-stage dry AMD, including preceding loss of RPE cell polarity, accumulation of acrolein, malondialdehyde, and 4-hydroxynonenal, photoreceptor loss, lipofuscin-laden subretinal melanophage infiltration, and complement activation. Treatment with α-tocopherol and ferrostatin-1 mitigated RPE degeneration, and shrunk mitochondria were observed in GPx4 deficient mice, suggesting involvement of ferroptosis. Unexpectedly, necrostatin-1s, an inhibitor of necroptosis, also ameliorated RPE degeneration, and activation of RIP3 and MLKL along with inactivation of caspase-8 was observed, indicating crosstalk between ferroptosis and necroptosis pathways. Our findings shed light on the intricate mechanisms underlying RPE degeneration in AMD and highlight GPx4/lipid peroxidation as potential therapeutic targets. RPE-specific ablation of GPx4 in mice provides a valuable tool for further elucidating the interplay between lipid peroxidation, cell death pathways, and AMD pathogenesis, offering new insights for preclinical research and therapeutic development targeting GA.

Emerging treatments for geographic atrophy and the impact on clinical management of age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of vision impairment in people over 50 years of age and has a great impact on quality of life as it affects central vision. Although there have been treatments available for the neovascular form of late AMD for decades, until now there have not been treatments available for the atrophic form of late AMD - geographic atrophy (GA). Recently, treatments acting on the complement pathway have been approved by the United States Food and Drug Administration, with other jurisdictions such as Australia considering their approval. Furthermore, there are many more potential treatments for GA currently in clinical trials. However, unlike the treatments for neovascular AMD, where clinicians have treated virtually all patients presenting with exudation, the decision to treat those with GA will be more nuanced and individualised. Longitudinal retinal imaging will be one important asset that will help tremendously when counselling patients, as through these images, the growth pattern of the atrophy can be determined. Even without individual prior imaging history, there are other imaging clues to help predict growth rates and threats to the fovea, and hence imminent vision loss. Optometrists have a critical role in this new era where GA treatments will be available, as they are often the first to have contact with GA patients. Insightful, well-informed counselling and appropriate referral for those seeking more information on potential treatment to confirm the diagnosis and perform baseline imaging at a location likely to undertake any future treatment will ensure that appropriate patients have had the best workup to be individually managed once these treatments arrive in Australia.

Quantitative comparison of automated OCT and conventional FAF-based geographic atrophy measurements in the phase 3 OAKS/DERBY trials.

With the approval of the first two substances for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD), a standardized monitoring of patients treated with complement inhibitors in clinical practice is needed. Optical coherence tomography (OCT) provides high-resolution access to the retinal pigment epithelium (RPE) and neurosensory layers, such as the ellipsoid zone (EZ), which further enhances the understanding of disease progression and therapeutic effects in GA compared to conventional fundus autofluorescence (FAF). In addition, artificial intelligence-based methodology allows the identification and quantification of GA-related pathology on OCT in an objective and standardized manner. The purpose of this study was to comprehensively evaluate automated OCT monitoring for GA compared to reading center-based manual FAF measurements in the largest successful phase 3 clinical trial data of complement inhibitor therapy to date. Automated OCT analysis of RPE loss showed a high and consistent correlation to manual GA measurements on conventional FAF. EZ loss on OCT was generally larger than areas of RPE loss, supporting the hypothesis that EZ loss exceeds underlying RPE loss as a fundamental pathophysiology in GA progression. Automated OCT analysis is well suited to monitor disease progression in GA patients treated in clinical practice and clinical trials.

Artificial intelligence for geographic atrophy: pearls and pitfalls.

PURPOSE OF REVIEW: This review aims to address the recent advances of artificial intelligence (AI) in the context of clinical management of geographic atrophy (GA), a vision-impairing late-stage manifestation of age-related macular degeneration (AMD). RECENT FINDINGS: Recent literature shows substantial advancements in the development of AI systems to segment GA lesions on multimodal retinal images, including color fundus photography (CFP), fundus autofluorescence (FAF) and optical coherence tomography (OCT), providing innovative solutions to screening and early diagnosis. Especially, the high resolution and 3D-nature of OCT has provided an optimal source of data for the training and validation of novel algorithms. The use of AI to measure progression in the context of newly approved GA therapies, has shown that AI methods may soon be indispensable for patient management. To date, while many AI models have been reported on, their implementation in the real-world has only just started. The aim is to make the benefits of AI-based personalized treatment accessible and far-reaching. SUMMARY: The most recent advances (pearls) and challenges (pitfalls) associated with AI methods and their clinical implementation in the context of GA will be discussed.

Therapeutic innovations for geographic atrophy: A promising horizon.

This mini review spotlights the most promising treatments for geographic atrophy, the advanced form of age-related macular degeneration, often resulting in severe and irreversible vision loss. The pathophysiology is complex, and various therapeutic strategies, including anticomplement therapies, gene therapies, cell-based interventions, and artificial intelligence-driven diagnostics are discussed. Anticomplement therapies (antifactors C3 and C5) showed promise in reducing the inflammatory response and the progression of the atrophy. Gene therapies, targeting specific genetic mutations, are under development to correct underlying defects and potentially reverse disease progression. Cell-based therapies are gaining momentum, with early studies indicating encouraging results in the replacement of damaged retinal pigment epithelium cells.

Informing Endpoints for Clinical Trials of Geographic Atrophy.

Geographic atrophy (GA), the non-neovascular advanced form of age-related macular degeneration, remains an important disease area in which treatment needs are currently unmet. Recent clinical trials using drugs that target the complement pathway have shown modest yet consistent reductions in GA expansion but without commensurate changes in measures of visual function. In this review, we summarize information from the wide range of studies describing the characteristics of GA morphology and enumerate the factors influencing the growth rates of lesions and the directionality of expansion. In addition, we review the relationship between GA growth and the various measures of vision that reflect changes in function. We consider the reasons for the discordance between the anatomical and functional endpoints in current use and discuss methods to align these key outcomes.

PATHWAYS TO GEOGRAPHIC ATROPHY IN NONNEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To characterize and quantify the precursor lesions of geographic atrophy in eyes with age-related macular degeneration. METHODS: A retrospective study of eyes with a minimum of 6-month follow-up before developing geographic atrophy. Evaluations included color and autofluorescence imaging, along with spectral-domain optical coherence tomography, employing definitions from the Consensus of Atrophy Meeting Group and Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group. RESULTS: There were 55 eyes of 44 patients, who had a mean age of 81.3 years at onset of atrophy; 35 (63.6%) were female. The mean duration of follow-up before and after the advent of geographic atrophy was 4.9 years and 1.2 years, respectively. Geographic atrophy was preceded by collapse of a druse in 41 eyes (74.5%). Of these, 29 (70.7%) were drusenoid pigment epithelial detachments. Among the eyes with regressing drusen, there were 9 with overlying vitelliform deposit, and all had concurrent subretinal drusenoid deposit; however, 19 of 30 eyes with no vitelliform deposit overlying the druse had concurrent subretinal drusenoid deposit, a difference that was significant ( P < 0.001). Regression of subretinal drusenoid deposit was found in 4 eyes (7.3%), regression of vitelliform deposit associated with subretinal drusenoid deposit in 5 (9.1%), and regression of vitelliform deposit in eyes concurrently harboring drusen was found in 3 (5.4%) and regression of vitelliform deposit alone in 2 (3.6%) at the site of eventual development of geographic atrophy. CONCLUSION: Geographic atrophy appears to develop from multiple pathways as manifested by the many precursor lesions, all various forms of extracellular deposit, that upon regression, result in a common end-stage appearance.

VEGF and ELAVL1/HuR protein levels are increased in dry and wet AMD patients. A new tile in the pathophysiologic mechanisms underlying RPE degeneration?

Age-related macular degeneration (AMD) is a common retinal pathology characterized by degeneration of macula's retinal pigment epithelium (RPE) and photoreceptors, visual impairment, or loss. Compared to wet AMD, dry AMD is more common, but lacks cures; therefore, identification of new potential therapeutic targets and treatments is urgent. Increased oxidative stress and declining antioxidant, detoxifying systems contribute to the pathophysiologic mechanisms underlying AMD. The present work shows that the Embryonic Lethal Abnormal Vision-Like 1/Human antigen R (ELAVL1/HuR) and the Vascular Endothelial Growth Factor (VEGF) protein levels are higher in the RPE of both dry and wet AMD patients compared to healthy subjects. Moreover, increased HuR protein levels are detected in the retina, and especially in the RPE layer, of a dry AMD model, the nuclear factor erythroid 2-related factor 2 (Nrf2) / peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) double knock-out mouse. The crosstalk among Nrf2, HuR and VEGF has been also studied in ARPE-19 cells in basal and stressful conditions related to the AMD context (i.e., oxidative stress, autophagy impairment, Nrf2 deficit), offering new evidence of the mutual influence between Nrf2 and HuR, of the dependence of VEGF expression and secretion by these two factors, and of the increased susceptibility of cells to stressful conditions in Nrf2- or HuR-impaired contexts. Overall, this study shows evidence of the interplay among Nrf2, HuR and VEGF, essential factors for RPE homeostasis, and represents an additional piece in the understanding of the complex pathophysiologic mechanisms underlying AMD.

Topographic Clinical Insights From Deep Learning-Based Geographic Atrophy Progression Prediction.

Purpose: To explore the contributions of fundus autofluorescence (FAF) topographic imaging features to the performance of convolutional neural network-based deep learning (DL) algorithms in predicting geographic atrophy (GA) growth rate. Methods: Retrospective study with data from study eyes from three clinical trials (NCT02247479, NCT02247531, NCT02479386) in GA. The algorithm was initially trained with full FAF images, and its performance was considered benchmark. Ablation experiments investigated the contribution of imaging features to the performance of the algorithms. Three FAF image regions were defined relative to GA: Lesion, Rim, and Background. For No Lesion, No Rim, and No Background datasets, a single region of interest was removed at a time. For Lesion, Rim, and Background Shuffled datasets, individual region pixels were randomly shuffled. For Lesion, Rim, and Background Mask datasets, masks of the regions were used. A Convex Hull dataset was generated to evaluate the importance of lesion size. Squared Pearson correlation (r2) was used to compare the predictive performance of ablated datasets relative to the benchmark. Results: The Rim region influenced r2 more than the other two regions in all experiments, indicating the most relevant contribution of this region to the performance of the algorithms. In addition, similar performance was observed for all regions when pixels were shuffled or only a mask was used, indicating intensity information was not independently informative without textural context. Conclusions: These ablation experiments enabled topographic clinical insights on FAF images from a DL-based GA progression prediction algorithm. Translational Relevance: Results from this study may lead to new insights on GA progression prediction.

C5 inhibitor avacincaptad pegol treatment for geographic atrophy: A comprehensive review.

Geographic atrophy (GA) remains a leading cause of central vision loss with no known cure. Until recently, there were no approved treatments for GA, often resulting in poor quality of life for affected patients. GA is characterized by atrophic lesions on the retina that may eventually threaten the fovea. Emerging treatments have demonstrated the ability to reduce the rate of lesion growth, potentially preserving visual function. Avacincaptad pegol (ACP; Astellas Pharma Inc), a complement component 5 inhibitor, is an FDA-approved treatment for GA that has been evaluated in numerous clinical trials. Here we review the current clinical trial landscape of ACP, including critical post hoc analyses that suggest ACP may reduce the risk of severe loss among patients with GA.

Geographic atrophy (GA) is an advanced form of eye disease age-related macular degeneration. In people with GA, light-sensitive cells at the back of the eye (the retina) start to die, forming lesions. GA lesions usually get bigger over time and can lead to blindness. New medicines are being studied that work by slowing the growth of GA lesions. Avacincaptad pegol (ACP) is one medicine that acts on the immune system and is designed to block the C5 protein, helping stop the immune system from attacking cells in the retina. Based on clinical studies, ACP was shown to slow the growth of GA over time and has been approved by the FDA. This review article summarizes research on ACP.

Microperimetry Characteristics of Regions With a Truly Nonresponding Location: Implications for Atrophic Age-Related Macular Degeneration.

Purpose: To understand the microperimetry response characteristics of regions with a truly nonresponding location, which will be useful when considering criteria for end-stage atrophic age-related macular degeneration (AMD). Methods: A simulation model was developed using data from 128 participants with bilateral large drusen at baseline seen over 36 months at 6-month intervals. One hundred thousand pairs of real-world microperimetry testing results were simulated separately with and without one truly nonresponding location, where the sensitivity of one randomly selected location for the former group was derived from the distribution of responses from a truly nonresponding location at the optic nerve head from 60 healthy participants. Results: Only 60% of the simulated test pairs with a truly nonresponding location had ≥1 location that was <0 decibel (dB) on both tests. In contrast, 91% of the simulated test pairs had ≥1 location that was ≤10 dB on both tests, and 87% had ≥1 location that was ≤10 dB on both tests and <0 dB for one of the tests. Of the simulated test pairs without a truly nonresponding location, there were 0.04%, 1.4%, and 0.4% that met these three above criteria, respectively. Conclusions: Regions with a truly nonresponding test location do not almost always show a repeatable absolute scotoma (<0 dB), but instead, much more often a deep visual sensitivity defect (≤10 dB), with or without having an absolute scotoma on one of the tests. These findings are crucial if functional criteria are to be considered as part of a definition of end-stage atrophic AMD.

[Use of artificial intelligence in geographic atrophy in age-related macular degeneration]. / Einsatz von künstlicher Intelligenz bei der geographischen Atrophie bei der altersabhängigen Makuladegeneration.

The first regulatory approval of treatment for geographic atrophy (GA) secondary to age-related macular degeneration in the USA constitutes an important milestone; however, due to the nature of GA as a non-acute, insidiously progressing pathology, the ophthalmologist faces specific challenges concerning risk stratification, making treatment decisions, monitoring of treatment and patient education. Innovative retinal imaging modalities, such as fundus autofluorescence (FAF) and optical coherence tomography (OCT) have enabled identification of typical morphological alterations in relation to GA, which are also suitable for the quantitative characterization of GA. Solutions based on artificial intelligence (AI) enable automated detection and quantification of GA-specific biomarkers on retinal imaging data, also retrospectively and over time. Moreover, AI solutions can be used for the diagnosis and segmentation of GA as well as the prediction of structure and function without and under GA treatment, thereby making a valuable contribution to treatment monitoring and the identification of high-risk patients and patient education. The integration of AI solutions into existing clinical processes and software systems enables the broad implementation of informed and personalized treatment of GA secondary to AMD.

Combination of optical coherence tomography-derived shape and texture features are associated with development of sub-foveal geographic atrophy in dry AMD.

Geographic atrophy (GA) is an advanced form of dry age-related macular degeneration (AMD) that leads to progressive and irreversible vision loss. Identifying patients with greatest risk of GA progression is important for targeted utilization of emerging therapies. This study aimed to comprehensively evaluate the role of shape-based fractal dimension features ( F fd ) of sub-retinal pigment epithelium (sub-RPE) compartment and texture-based radiomics features ( F t ) of Ellipsoid Zone (EZ)-RPE and sub-RPE compartments for risk stratification for subfoveal GA (sfGA) progression. This was a retrospective study of 137 dry AMD subjects with a 5-year follow-up. Based on sfGA status at year 5, eyes were categorized as Progressors and Non-progressors. A total of 15 shape-based F fd of sub-RPE surface and 494 F t from each of sub-RPE and EZ-RPE compartments were extracted from baseline spectral domain-optical coherence tomography scans. The top nine features were identified from F fd and F t feature pool separately using minimum Redundancy maximum Relevance feature selection and used to train a Random Forest (RF) classifier independently using three-fold cross validation on the training set ( S t , N = 90) to distinguish between sfGA Progressors and Non-progressors. Combined F fd and F t was also evaluated in predicting risk of sfGA progression. The RF classifier yielded AUC of 0.85, 0.79 and 0.89 on independent test set ( S v , N = 47) using F fd , F t , and their combination, respectively. Using combined F fd and F t , the improvement in AUC was statistically significant on S v with p-values of 0.032 and 0.04 compared to using only F fd and only F t , respectively. Combined F fd and F t appears to identify high-risk patients. Our results show that FD and texture features could be potentially used for predicting risk of sfGA progression and future therapeutic response.

Quantifying Geographic Atrophy in Age-Related Macular Degeneration: A Comparative Analysis Across 12 Deep Learning Models.

Purpose: AI algorithms have shown impressive performance in segmenting geographic atrophy (GA) from fundus autofluorescence (FAF) images. However, selection of artificial intelligence (AI) architecture is an important variable in model development. Here, we explore 12 distinct AI architecture combinations to determine the most effective approach for GA segmentation. Methods: We investigated various AI architectures, each with distinct combinations of encoders and decoders. The architectures included three decoders-FPN (Feature Pyramid Network), UNet, and PSPNet (Pyramid Scene Parsing Network)-and serve as the foundation framework for segmentation task. Encoders including EfficientNet, ResNet (Residual Networks), VGG (Visual Geometry Group) and Mix Vision Transformer (mViT) have a role in extracting optimum latent features for accurate GA segmentation. Performance was measured through comparison of GA areas between human and AI predictions and Dice Coefficient (DC). Results: The training dataset included 601 FAF images from AREDS2 study and validation included 156 FAF images from the GlaxoSmithKline study. The mean absolute difference between grader measured and AI predicted areas ranged from -0.08 (95% CI = -1.35, 1.19) to 0.73 mm2 (95% CI = -5.75,4.29) and DC between 0.884-0.993. The best-performing models were UNet and FPN frameworks with mViT, and the least-performing models were PSPNet framework. Conclusions: The choice of AI architecture impacts GA segmentation performance. Vision transformers with FPN and UNet architectures demonstrate stronger suitability for this task compared to Convolutional Neural Network- and PSPNet-based models. Selecting an AI architecture must be tailored to the specific goals of the project, and developers should consider which architecture is ideal for their project.

Sequence of Morphological Changes Preceding Atrophy in Intermediate AMD Using Deep Learning.

Purpose: Investigating the sequence of morphological changes preceding outer plexiform layer (OPL) subsidence, a marker preceding geographic atrophy, in intermediate AMD (iAMD) using high-precision artificial intelligence (AI) quantifications on optical coherence tomography imaging. Methods: In this longitudinal observational study, individuals with bilateral iAMD participating in a multicenter clinical trial were screened for OPL subsidence and RPE and outer retinal atrophy. OPL subsidence was segmented on an A-scan basis in optical coherence tomography volumes, obtained 6-monthly with 36 months follow-up. AI-based quantification of photoreceptor (PR) and outer nuclear layer (ONL) thickness, drusen height and choroidal hypertransmission (HT) was performed. Changes were compared between topographic areas of OPL subsidence (AS), drusen (AD), and reference (AR). Results: Of 280 eyes of 140 individuals, OPL subsidence occurred in 53 eyes from 43 individuals. Thirty-six eyes developed RPE and outer retinal atrophy subsequently. In the cohort of 53 eyes showing OPL subsidence, PR and ONL thicknesses were significantly decreased in AS compared with AD and AR 12 and 18 months before OPL subsidence occurred, respectively (PR: 20 µm vs. 23 µm and 27 µm [P < 0.009]; ONL, 84 µm vs. 94 µm and 98 µm [P < 0.008]). Accelerated thinning of PR (0.6 µm/month; P < 0.001) and ONL (0.8 µm/month; P < 0.001) was observed in AS compared with AD and AR. Concomitant drusen regression and hypertransmission increase at the occurrence of OPL subsidence underline the atrophic progress in areas affected by OPL subsidence. Conclusions: PR and ONL thinning are early subclinical features associated with subsequent OPL subsidence, an indicator of progression toward geographic atrophy. AI algorithms are able to predict and quantify morphological precursors of iAMD conversion and allow personalized risk stratification.

Progressive Choriocapillaris Changes on Optical Coherence Tomography Angiography Correlate With Stage Progression in AMD.

Purpose: We investigated the association between inner choroid flow deficit percentage (IC-FD%) using swept-source optical coherence tomography angiography (SS-OCTA) and progression of AMD. Methods: Retrospective, observational study including 64 eyes (42 participants) with early or intermediate AMD at baseline. Participants had two or more consecutive swept-source optical coherence tomography angiography covering a period of at least 18 months. Demographics, visual acuity, and AMD staging based on Beckman classification were reviewed. OCT was analyzed for hyperreflective foci, subretinal drusenoid deposits, hyporeflective drusen cores, and subfoveal choroidal thickness. IC-FD% was measured within the central 3- and 6-mm using a 16-µm slab, after compensation and binarization (Phansalkar method). Mixed-effects Cox regression models assessed the association between imaging biomarkers and AMD progression. Results: During follow-up (37 ± 9 months), 4 eyes with early AMD (31%) progressed to intermediate AMD and 30 (59%) eyes with intermediate AMD developed late AMD (19 geographic atrophy; 11 wet AMD). Baseline hyporeflective drusen core was associated with geographic atrophy development (P < 0.01), whereas greater IC-FD% (3-mm) was associated with wet AMD (P = 0.03). Time-varying analysis showed that faster subfoveal choroidal thickness reduction and IC-FD% (6-mm) increase were associated with geographic atrophy onset (P < 0.05), whereas IC-FD% (3-mm) increase was associated with wet AMD (P = 0.03). Notably, greater IC-FD% increases in the 3 mm (area under the curve = 0.72) and 6 mm (area under the curve = 0.89) were better predictive of wet AMD and geographic atrophy development, respectively. Conclusions: Our longitudinal IC-FD% assessment emphasizes the role of progressive choriocapillaris changes as a biomarker for AMD progression. Our findings support that widespread choriocapillaris alterations (6 mm) may precede progression to geographic atrophy, whereas more central choriocapillaris loss (3 mm) may provide an ischemic stimulus for wet AMD.