Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision. Unfortunately, the specific pathogenesis remains unclear, and effective early treatment options are consequently lacking. The microbiome is defined as a large ecosystem of microorganisms living within and coexisting with a host. The intestinal microbiome undergoes dynamic changes owing to age, diet, genetics, and other factors. Such dysregulation of the intestinal flora can disrupt the microecological balance, resulting in immunological and metabolic dysfunction in the host, and affecting the development of many diseases. In recent decades, significant evidence has indicated that the intestinal flora also influences systems outside of the digestive tract, including the brain. Indeed, several studies have demonstrated the critical role of the gut-brain axis in the development of brain neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Similarly, the role of the "gut-eye axis" has been confirmed to play a role in the pathogenesis of many ocular disorders. Moreover, age-related macular degeneration and many brain neurodegenerative diseases have been shown to share several risk factors and to exhibit comparable etiologies. As such, the intestinal flora may play an important role in age-related macular degeneration. Given the above context, the present review aims to clarify the gut-brain and gut-eye connections, assess the effect of intestinal flora and metabolites on age-related macular degeneration, and identify potential diagnostic markers and therapeutic strategies. Currently, direct research on the role of intestinal flora in age-related macular degeneration is still relatively limited, while studies focusing solely on intestinal flora are insufficient to fully elucidate its functional role in age-related macular degeneration. Organ-on-a-chip technology has shown promise in clarifying the gut-eye interactions, while integrating analysis of the intestinal flora with research on metabolites through metabolomics and other techniques is crucial for understanding their potential mechanisms.

Hallmark findings in age-related macular degeneration (AMD) include the accumulation of extracellular lipid and vasodegeneration of the choriocapillaris. Choroidal inflammation has long been associated with AMD, but little is known about the immune landscape of the human choroid. Using 3D multiplex immunofluorescence, single-cell RNA sequencing, and flow cytometry, we unravel the cellular composition and spatial organization of the human choroid and the immune cells within it. We identify two populations of choroidal macrophages with distinct FOLR2 expression that account for the majority of myeloid cells. FOLR2+ macrophages predominate in the nondiseased eye, express lipid-handling machinery, uptake lipoprotein particles, and contain high amounts of lipid. In AMD, FOLR2+ macrophages are decreased in number and exhibit dysfunctional lipoprotein metabolism. In mice, FOLR2+ macrophages are negative for the postnatal fate-reporter Ms4a3, and their depletion causes an accelerated AMD-like phenotype. Our results show that prenatally derived resident macrophages decline in AMD and are implicated in multiple hallmark functions known to be compromised in the disease.

Gene therapy is an innovative medical approach that offers new treatment options for congenital and acquired diseases by transferring, correcting, inactivating or regulating genes to supplement, replace or modify a gene function. The approval of voretigene neparvovec (Luxturna), a gene therapy for RPE65-associated retinopathy, has marked a milestone for the field of retinal gene therapy, but has also helped to accelerate the development of gene therapies for genetic diseases affecting other organs. Voretigene neparvovec is a vector based on adeno-associated virus (AAV) that delivers a functional copy of RPE65 to supplement the missing function of this gene. The AAV-based gene delivery has proven to be versatile and safe for the transfer of genetic material to retinal cells. However, challenges remain in treating additional inherited as well as acquired retinopathies with this technology. Despite the high level of activity in this field, no other AAV gene therapy for retinal diseases has been approved since voretigene neparvovec. Ongoing research focuses on overcoming the current restraints through innovative strategies like AAV capsid engineering, dual-AAV vector systems, or CRISPR/Cas-mediated genome editing. Additionally, AAV gene therapy is being explored for the treatment of complex acquired diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR) by targeting molecules involved in the pathobiology of the degenerative processes. This review outlines the current state of retinal gene therapy, highlighting ongoing challenges and future directions.

Age-related macular degeneration (AMD) represents a major global health burden, with current estimates suggesting that up to 200 million people are affected globally. While effective treatments exist for the exudative form of the disease termed choroidal neovascular AMD, there remain challenges associated with long-term responses to treatment and the ongoing parallel development of the non-exudative form of AMD. Here, we sought to develop an approach for long-term delivery of both aflibercept, a decoy receptor that neutralises vascular endothelial growth factor and a concomitant treatment focused on treating the non-exudative form of AMD. To this end, we developed a series of induced pluripotent stem cell (iPS)-derived retinal pigment epithelial (RPE) cell lines that stably expressed aflibercept and/or sCD59. These cell lines were shown to produce high concentrations of both proteins. Sub-retinal injection of enhanced RPE cells potently prevented leakage of neovascular lesions in the JR5558 mouse model of retinal and choroidal neovascularization. Early results described here suggest that enhanced iPS-derived RPE cells could represent a novel approach to the long-term delivery of therapeutic agents to the eye.

Extracellular lipoprotein aggregation is a critical event in age-related macular degeneration (AMD) pathogenesis. In this study, we sought to analyze associations between clinical and genetic-based factors related to lipoprotein metabolism and risk for AMD in the All of Us research program.

Cross-sectional retrospective data analysis.

A total of 5028 healthy participants and 2328 patients with AMD from All of Us.

Participants with and without AMD were age, race, and sex matched in a 1:2 ratio, respectively. Smoking status, history of hyperlipidemia, and statin use were extracted in a binary manner. Statin use was further subcategorized into hepatically versus nonhepatically metabolized statins. Laboratory values for low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TGs) were also extracted, and outliers were excluded from analysis. The PLINK toolkit was used to extract single nucleotide polymorphisms (SNPs) associated with LDL and HDL dysregulation, as published in prior work. Odds ratio curves were computed to assess the risk between LDL, TG, and HDL versus AMD. All clinical and genetic variables were input into a multivariable logistic regression model, and odds ratios and P values were generated.

Statistical significance of risk factors for AMD, thresholded at P ≤ 0.05.

On multivariable regression analysis, statin use and low and high HDL were significantly associated with increased AMD risk (P < 0.001 for all variables). Additionally, the multivariable regression implicated HDL-associated SNP's increased risk for AMD. Last, LPA was identified (P = 0.007) as a novel SNP associated with increased AMD risk.

There exists a U-shaped relationship between HDL and AMD risk, such that high and low HDL are significantly associated with increased AMD risk. Additionally, SNPs associated with HDL metabolism are associated with AMD risk. This analysis further establishes the role of HDL in AMD pathogenesis.

Proprietary or commercial disclosure may be found after the references.

To identify genetic determinants specific to reticular pseudodrusen (RPD) compared with drusen.

Genome-wide association study (GWAS) SUBJECTS: Participants with RPD, drusen, and controls from the UK Biobank (UKBB), a large, multisite, community-based cohort.

Participants with RPD, drusen, and controls from the UK Biobank (UKBB), a large, multisite, community-based cohort, were included. A deep learning framework analyzed 169,370 optical coherence tomography (OCT) volumes to identify cases and controls within the UKBB. Five retina specialists validated the cohorts using OCT and color fundus photographs. Several GWAS were undertaken utilizing the quantity and presence of RPD and drusen. Genome-wide significance was defined as P < 5e-8.

Genetic associations were examined with the number of RPD and drusen within 'pure' cases, where only RPD or drusen were present in either eye. A candidate approach assessed 46 previously known AMD loci. Secondary GWAS were conducted for number of RPD and drusen in mixed cases, and binary case-control analyses for pure RPD and pure drusen.

The study included 1787 participants: 1037 controls, 361 pure drusen, 66 pure RPD, and 323 mixed cases. The primary pure RPD GWAS identified four genome-wide significant loci: rs11200630 near ARMS2-HTRA1 (P = 1.9e-09), rs79641866 at PARD3B (P = 1.3e-08), rs143184903 near ITPR1 (P = 8.1e-09), and rs76377757 near SLN (P = 4.3e-08). The latter three are uncommon variants (minor allele frequency <5%). A significant association at the CFH locus was also observed using a candidate approach (P = 1.8e-04). For pure drusen, two loci reached genome-wide significance: rs10801555 at CFH (P = 6.0e-33) and rs61871744 at ARMS2-HTRA1 (P = 4.2e-20).

The study highlights a clear association between the ARMS2-HTRA1 locus and higher RPD load. Although the CFH locus association did not achieve genome-wide significance, a suggestive link was observed. Three novel associations unique to RPD were identified, albeit for uncommon genetic variants. Further studies with larger sample sizes are needed to explore these findings.

Age-related macular degeneration (AMD) is the leading cause of central vision loss in older adults and is projected to affect approximately 400 million individuals worldwide by 2040. Its pathological characteristics include retinal extracellular deposits, such as drusen, which trigger photoreceptor degeneration and damage to the retinal pigment epithelium (RPE), resulting in irreversible vision loss. The pathogenesis of AMD involves genetic, environmental, and aging-related factors. Anti-vascular endothelial growth factor (anti-VEGF) therapy for wet AMD significantly inhibits choroidal neovascularization and delays visual deterioration. However, its high cost, frequent injections, and poor patient compliance limit application, and there remains no effective intervention for dry AMD. In recent years, emerging strategies, such as gene therapy, stem cell therapy, and nanotechnology-based drug delivery systems, offer hope for slowing disease progression by improving targeting, drug stability, and reducing treatment frequency. Nanoparticles, including polymeric and lipid systems, have shown promise for enhancing drug delivery and bioavailability, particularly for dry AMD, where existing therapies are inadequate. These strategies also have the potential to improve patient compliance. This review summarizes AMD epidemiology and examines the limitations of current therapies. It emphasizes the mechanisms and clinical advancements of gene therapy, stem cell therapy, and nanotechnology in AMD treatment. These emerging technologies offer promising opportunities for precision medicine and lay a solid foundation for the future development of multifaceted therapeutic strategies.

We assessed the associations of macular layer thicknesses, measured using spectral-domain (SD) OCT, with incident age-related macular degeneration (AMD) and AMD polygenic risk scores (PRSs).

Population-based cohort study.

A total of 653 participants from the ALIENOR study, with biennial eye imaging from 2009 through 2024.

Macular layer thicknesses of 8 distinct layers were automatically segmented based on SD-OCT imaging. Total and pathway-specific PRSs were calculated from previous AMD genome-wide association studies summary statistics. Associations of macular layer thicknesses with incident intermediate and advanced AMD were analyzed using time-dependent Cox proportional hazards models. Associations of macular layer thicknesses with PRS were assessed using linear mixed models.

Incident intermediate and advanced AMD based on fundus color photographs and SD-OCT.

Mean age at first OCT examination of the 653 participants was 82.2 ± 4.2 years, 61.3% of which were women. In multivariable adjusted models, incident intermediate AMD was associated with thicker retinal pigment epithelium (RPE)-Bruch membrane (BM) complex in the 1-mm central circle (hazard ratio [HR], 1.13 for 1-μm increase; P = 8.08 × 10-4 with false discovery rate [FDR] correction). Incident advanced AMD was associated with thicker RPE-BM complex in both the central (HR, 1.09; PFDR = 0.005) and inner circle (1- to 3 mm; HR, 1.28; PFDR = 1.61 × 10-5). Over the study period, RPE-BM complex thickening in the inner circle was more pronounced in individuals with high total PRS (β = 0.06 μm/year for 1-standard deviation increase; PFDR = 1.61 × 10-10), high complement pathway PRS (β = 0.04 μm/year; PFDR = 3.23 × 10-5), high lipid pathway PRS (β = 0.03 μm/year; PFDR = 3.74 × 10-4), and ARMS2 (β = 0.03 μm/year, PFDR = 0.002). High total PRS and high complement-specific PRS were associated with thinner photoreceptor segment layer (PSL) at baseline and longitudinal thinning of the outer nuclear layer.

These findings highlight RPE-BM complex thickening in the pathophysiologic sequence of AMD. Further longitudinal studies are needed, in particular to determine the value of RPE-BM thickening and PSL thinning measured using SD-OCT for the clinical follow-up of patients with AMD.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Although polygenic risk scores (PRSs) have been developed for age-related macular degeneration (AMD), it is not known whether these scores are associated with impairment of visual functions in older individuals with healthy macula. We evaluated age-related changes in visual function in people aged 55 years or above with healthy macula and determined the associations of age-related visual function changes with AMD PRS in people with healthy macula.

Participants aged 55 years or above with healthy macula and a comparative group of people with early or intermediate AMD from the Northern Ireland Sensory Ageing study were included. 45 SNPs were included for PRS calculation.

A total of 470 participants with healthy macula were included (Beckman grade 0 or 1). The comparator group consisted of participants with early AMD (n = 87) or intermediate AMD (n = 48). All visual functions except metrics of central visual field assessment showed a significant decline with age in adjusted linear regression models. Rod intercept time (RIT) was the only visual function significantly associated with PRS with Beta = 0.12 (95% confidence interval: 0.01-0.23), P = 0.03. A PRS integrated model achieved the highest area under the receiver operating characteristic curve (AUC) of 0.803 (0.732 to 0.874) to distinguish between normal or increased RIT.

We observed a significant decline in multiple visual functions with increasing age. However, PRS was significantly associated with RIT only, highlighting the genetic association of age-related decline in rod function.

Age-related macular degeneration (AMD) is one of the most prevalent eye diseases among the ageing population worldwide. It is a leading cause of blindness in individuals over 55, particularly in industrialised Western countries. The prevalence of AMD increases with age, and genetic factors and environmental influences are believed to contribute to its development. Among the environmental factors, diet plays a significant role in AMD. This review explores the association between dietary components, dietary patterns and AMD. Various nutrients, non-nutrient substances and dietary models that have the potential to counteract oxidative stress and inflammation, which are underlying mechanisms of AMD, are discussed. Consuming fruits, vegetables, fish and seafood, whole grains, olive oil, nuts and low-glycaemic-index foods has been highlighted as beneficial for reducing the risk of AMD. Adhering to the Mediterranean diet, which encompasses these elements, can be recommended as a dietary pattern for AMD. Furthermore, the modulation of the gut microbiota through dietary interventions and probiotics has shown promise in managing AMD.

Age-related macular degeneration (AMD) and Alzheimer's disease (AD), two prevalent neurodegenerative disorders, share overlapping pathophysiological features yet lack cross-disease therapeutic strategies. This study systematically investigates their parallel genes and shared molecular mechanisms to identify potential therapeutic targets for dry AMD, a condition with limited treatment options.

Transcriptomic datasets for AMD (GSE155154) and AD (GSE95587) were retrieved from the GEO database. AMD tissues were stratified into four subgroups: macular retina (MR), macular choroid/RPE/sclera (MCRS), peripheral retina (PR), and peripheral choroid/RPE/sclera (PCRS). Common differentially expressed genes (DEGs) were identified and analyzed via functional enrichment (GO, KEGG), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks. Drug-gene interactions and competing endogenous RNA (ceRNA) networks were constructed to prioritize therapeutic targets. Key hub genes were experimentally validated in a sodium iodate-induced AMD murine model using RT-qPCR.

Comparative analysis revealed 89, 56, 4, and 130 common DEGs between AD and MR, MCRS, PR, and PCRS subgroups, respectively. Neuroactive ligand-receptor interactions were prioritized in MR/MCRS-AD analyses, while extracellular matrix organization emerged as the dominant pathway in PCRS-AD comparisons. GSEA identified conserved the TNFα signaling pathway via NF-κB across both diseases. PCRS exhibited consistent expression trends for shared genes and pathways with AD. Computational screening prioritized seven druggable targets (COL1A1, COL1A2, COL3A1, MMP2, MMP9, VCAN, ITGA5) with dual therapeutic potential, along with a reconstructed circRNA (circRNA_002179)-miRNA (miR-124)-mRNA (VCAN) regulatory axis. Experimental validation in a sodium iodate-induced AMD murine model confirmed region-specific dysregulation: hub genes were significantly downregulated in MCRS but upregulated in PCRS.

Our study delineates both convergent and divergent molecular landscapes of AMD and AD, with PCRS emerging as a critical locus for shared pathophysiology. These findings bridge a critical gap in understanding AMD-AD comorbidity, offering actionable strategies for targeted drug development.

ObjectiveThe response to intravitreal brolucizumab on diabetic macular edema (DME) and macular ischemia was studied in treatment-refractory and treatment-naïve patients.MethodsPatients with either recalcitrant (group 1) or treatment-naïve (group 2) DME were studied before and after intravitreal brolucizumab. All patients underwent a comprehensive ophthalmological examination including optical coherence tomography (OCT) and OCT-angiography (OCT-A). We compared the DME and macular/choriocapillaris ischemia before and after the loading dose.ResultsA total of 33 eyes of 26 patients were examined. 18 eyes were switched to brolucizumab, 15 eyes were treatment naive. All eyes responded with anatomical and functional improvement: group 1: 391 vs 298 μm (p = 0.005), 0.6 ± 0.4 logMAR vs. 0.4 ± 0.4 logMAR) (p = 0.01), group 2: 430 vs 281 μm (p = 0.0007), 0.5 ± 0.2 logMAR vs. 0.2 ± 0.2 logMAR (p = 0.004). In group 2 there was also significant improvement in retinal vascular parameters, especially in the central and inner circles of the ETDRS grid: central capillary density 6.55 vs 9.03 mm/mm2 (p = 0.008), inner 11.2 vs 13, 9 mm/mm2 (p = 0.02), central perfusion density 15.5% vs 20.7% (p = 0.02). Choriocapillaris flow deficit (CCFD%) also improved after the loading dose (40.3 vs. 35.3, p = 0.03). Although not statistically significant, there was also an improved foveal circularity.ConclusionIntravitreal brolucizumab leads to significant functional and anatomical improvement in diabetic macular edema and has also a beneficial effect on macular ischemia as shown by improvement in both retinal and choroidal perfusion.

Polygenic risk scores (PRS) have ushered in a new era in genetic epidemiology, offering insights into individual predispositions to a wide range of diseases. However, despite recent marked enhancements in predictive power, PRS-based models still need to overcome several hurdles before they can be broadly applied in the clinic. Chiefly, they need to achieve sufficient accuracy, easy interpretability and portability across diverse populations. Leveraging trans-ancestry genome-wide association study (GWAS) meta-analysis, we generated novel, diverse summary statistics for 30 medically-related traits and benchmarked the performance of six existing PRS algorithms using UK Biobank. We built an ensemble model using logistic regression to combine outputs of top-performing algorithms and validated it on the diverse eMERGE and PAGE MEC cohorts. It surpassed current state-of-the-art PRS models, with minimal performance drops in external cohorts, indicating good calibration. To enhance predictive accuracy for clinical application, we incorporated easily-accessible clinical characteristics such as age, gender, ancestry and risk factors, creating disease prediction models intended as prospective diagnostic tests, with easily interpretable positive or negative outcomes. After adding clinical characteristics, 12 out of 30 models surpassed 80% AUC. Further, 25 traits exceeded the diagnostic odds ratio (DOR) of five, and 19 traits exceeded DOR of 10 for all ancestry groups, indicating high predictive value. Our PRS model for coronary artery disease identified 55-80 times more true coronary events than rare pathogenic variant models, reinforcing its clinical potential. The polygenic component modulated the effect of high-risk rare variants, stressing the need to consider all genetic components in clinical settings. These findings show that newly developed PRS-based disease prediction models have sufficient accuracy and portability to warrant consideration of being used in the clinic.

Age-related macular degeneration (AMD) is a leading cause of central vision loss, progressively impairing the retina and affecting millions worldwide. By 2040, global cases of AMD are projected to reach 300 million, posing a significant public health challenge. While early AMD may only cause mild visual impairment, advanced stages, particularly neovascular (wet) and non-neovascular (dry) AMD, can lead to severe vision loss or legal blindness, substantially affecting daily life. The introduction of anti-angiogenic therapies has revolutionized wet AMD treatment, offering a high probability of preserving or improving vision. However, these therapies do not halt AMD progression, and no definitive treatments exist for dry AMD. The limitations of current therapies, such as frequent injections and treatment resistance, underscore the urgent need for novel strategies. Gene therapy, which has shown success in treating other hereditary retinal diseases, offers a promising long-term solution for AMD by targeting retinal cells to produce therapeutic proteins. This review explores the potential of gene therapy for AMD, examining recent clinical trials and future treatment directions.

High-temperature requirement protein A1 (HTRA1) is a secreted serine protease with diverse substrates, including extracellular matrix proteins, proteins involved in amyloid deposition, and growth factors. Accordingly, HTRA1 has been implicated in a variety of neurodegenerative diseases including a leading cause of blindness in the elderly, age-related macular degeneration (AMD). In fact, genome wide association studies have identified that the 10q26 locus which contains HTRA1 confers the strongest genetic risk factor for AMD. A recent study has suggested that AMD-associated risk alleles in HTRA1 correlate with a significant age-related defect in HTRA1 synthesis in the retinal pigmented epithelium (RPE) within the eye, possibly accounting for AMD susceptibility. Thus, we sought to identify small molecule enhancers of HTRA1 transcription and/or protein abundance using an unbiased high-throughput screening approach. To accomplish this goal, we used CRISPR/Sp.Cas9 engineering to introduce an 11 amino acid luminescent peptide tag (HiBiT) onto the C-terminus of HTRA1 in immortalized ARPE-19 cells. Editing was very efficient (~88%), verified by genomic DNA analysis, short interfering RNA (siRNA), and HiBiT blotting. Nineteen-hundred and twenty compounds from two libraries were screened. An azo compound with reported anti-amyloidogenic and cardioprotective activity, Chicago Sky Blue 6B (CSB), was identified as an enhancer of endogenous HTRA1 secretion (2.0 ± 0.3 fold) and intracellular levels (1.7 ± 0.2 fold). These results were counter-screened using HiBiT complement factor H (CFH) edited ARPE-19 cells, verified using HiBiT blotting, and were not due to HTRA1 transcriptional changes. Importantly, serine hydrolase activity-based protein profiling (SH-ABPP) demonstrated that CSB does not affect HTRA1's specific activity. However, interestingly, in follow-up studies, Congo Red, another azo compound structurally similar to CSB, also substantially increased intracellular HTRA1 levels (up to 3.6 ± 0.3 fold) but was found to significantly impair HTRA1 enzymatic reactivity (0.45 ± 0.07 fold). Computational modeling of potential azo dye interaction with HTRA1 suggests that CSB and Congo Red can bind to the non-catalytic face of the trimer interface but with different orientation tolerances and interaction energies. These studies identify select azo dyes as HTRA1 chemical probes which may serve as starting points for future HTRA1-centered small molecule therapeutics.

The main challenge in dissecting the cells and pathways involved in the pathogenesis of age-related macular degeneration (AMD) is the highly heterogeneous and dynamic nature of the retinal microenvironment. This study aimed to describe the comprehensive landscape of the dry AMD (dAMD) model and identify the key cell cluster contributing to dAMD. We identified a subset of Müller cells that express high levels of Sox2, which play crucial roles in homeostasis and neuroprotection in both mouse models of AMD and patients with dAMD. Additionally, the number of Sox2+ Müller cells decreased significantly during the progression of AMD, indicating these cells were damaged and underwent cell death. Interestingly, ferroptosis and apoptosis were identified as contributors to the damage of Sox2+ Müller cells. Our findings are potentially valuable not only for advancing the current understanding of dAMD progression but also for the development of treatment strategies through the protection of Müller cells.

Alzheimer's disease (AD) and age-related macular degeneration (AMD) represent the leading causes of dementia and vision impairment in the elderly, respectively. The retina is an extension of the brain, yet these two central nervous system (CNS) compartments are often studied separately. Despite affecting cognition vs. vision, AD and AMD share neuroinflammatory pathways. By comparing these diseases, we can identify converging immune mechanisms and potential cross-applicable therapies. Here, we review immune mechanisms highlighting the shared and distinct aspects of these two age-related neurodegenerative conditions, focusing on responses to hallmark disease manifestations, the opposite role of overlapping immune risk loci, and potential unified therapeutic approaches. We also discuss unique tissue requirements that may dictate different outcomes of conserved immune mechanisms and how we can reciprocally utilize lessons from AD therapeutics to AMD. Looking forward, we suggest promising directions for research, including the exploration of regenerative medicine, gene therapies, and innovative diagnostics.

Ocular drug delivery is a significant challenge due to the intricate anatomy of the eye and the various physiological barriers. Conventional therapeutic approaches, while effective to some extent, often fall short in effectively targeting ocular diseases, resulting in suboptimal therapeutic outcomes due to factors such as poor ocular bioavailability, frequent dosing requirements, systemic side effects, and limited penetration through ocular barriers. This review elucidates the eye's intricate anatomy and physiology, prevalent ocular diseases, traditional therapeutic modalities, and the inherent pharmacokinetic and pharmacodynamic limitations associated with these modalities. Subsequently, it delves into nanotechnology-based solutions, presenting breakthroughs in nanoformulations such as nanocrystals, liposomes, dendrimers, and nanoemulsions that have demonstrated enhanced drug stability, controlled release, and deeper ocular penetration. Additionally, it explores a range of nanosized carriers, including nano-structured lipid carriers, hydrogels, nanogels, nanoenzymes, microparticles, conjugates, exosomes, nanosuspensions, viral vectors, and polymeric nanoparticles, and their applications. Unique insights include emerging innovations such as nanowafers and transcorneal iontophoresis, which indicate paradigm shifts in non-invasive ocular drug delivery. Furthermore, it sheds light on the advantages and limitations of these nanotechnology-based platforms in addressing the challenges of ocular drug delivery. Though nano-based drug delivery systems are drawing increasing attention due to their potential to enhance bioavailability and therapeutic efficacy, the review ends up emphasizing the imperative need for further research to drive innovation and improve patient outcomes in ophthalmology.

Age-related macular degeneration (AMD) is a complex, multifactorial retinal degenerative disease that is influenced by both genetic and environmental factors. However, the strongest risk factor for AMD is advanced age. Several physiological processes are observed in aging tissues including a low level of chronic inflammation (inflammaging), changed lipid and energy metabolism, and senescence. Nevertheless, whereas everyone ages, only a subset of the population develops AMD. The purpose of this review is to delineate the differences on a cellular and molecular level between natural aging changes and those observed in AMD. We provide a unique perspective on how genetic and environmental components modulate aging in the eye, as well as the specific role of the aging RPE and retina in the pathogenesis of AMD. Topics discussed include the mechanism of aging and its relation to the mechanism of AMD, current animal models that can be used to recapitulate some aspects of the pathology, and potential interventions that shift the balance towards healthy aging and therefore attenuate, prevent or delay the initiation of the disease.

Genome-wide association studies have been remarkably successful in identifying genetic variants associated with age-related macular degeneration (AMD), demonstrating a strong genetic component largely driven by common variants. However, progress in translating these genetic findings into a deeper understanding of disease mechanisms and new therapies has been slow. Slow progress in this area can be attributed to limited knowledge of the functional impact of AMD-associated non-coding variants on gene function, the molecular mechanisms and cell types underlying disease. This review offers a comprehensive overview of functional genomics approaches to uncover the genetic, epigenetic, cellular and molecular mechanisms underlying AMD and outlines future directions for research.

To explore the causal associations among circulating proteins, plasma metabolites, and age-related macular degeneration (AMD).

We employed Mendelian randomization (MR) analysis and colocalization analysis to discern the causal relationship between proteomes and AMD. This investigation utilized data from protein quantitative trait loci (pQTL) studies in deCODE and the UK Biobank. Additionally, plasma metabolite-related genome-wide association studies (GWAS) data and AMD-related GWAS data were incorporated.

Our findings confirmed a potential causal relationship between cytoplasmic tryptophanyl-tRNA synthetase 1 (WARS1) and a higher risk of AMD. The observed causal impact of WARS1 on the two subtypes of AMD (dry and wet) align consistently with the aforementioned outcomes. Three plasma metabolites-N-acetyl-kynurenine, N-acetyltyrosine, and caproate (6:0)-were identified as mediators of the causal effect of WARS1 on AMD, and subgroup analysis revealed that N-acetyltyrosine is a specific negative metabolite associated with WARS1 and dry AMD, whereas X-16580 is a specific positive metabolite linked to WARS1 and wet AMD.

The outcomes of this study suggest a potential causal role of specific circulating proteins in AMD and identified the mediating role of plasma metabolites between WARS1 and AMD by integrating multiple genetic analyses. Nevertheless, further research is essential to validate and strengthen these conclusions.

This study establishes the causal role of specific circulating proteins in AMD and identified the mediating role of plasma metabolites between WARS1 and AMD.

Age-related macular degeneration (AMD) is a leading cause of blindness among older adults worldwide, but treatment options are limited. Genetics studies have implicated the CFH locus, containing CFH and five CFHR genes, CFHR1-5, in AMD. While CFH has been robustly linked with AMD risk, potential additional roles for the CFHR genes remain unclear, obscured by strong linkage disequilibrium across the locus. Investigating rare coding variants can help to identify causal genes in such regions. We used whole-exome sequencing data from 406,952 UK Biobank participants to examine AMD associations with genes at the CFH locus. For each gene, we used burden testing to examine associations of rare (minor-allele frequency [MAF] < 1%) predicted loss-of-function (pLoF) and predicted damaging missense variants with AMD. We considered "broadly defined AMD" (ICD-10 35.3; ncases = 10,700) and "strictly defined AMD" (dry or wet AMD; ncases = 346). Adjusting for CFH-region variants known to independently associate with AMD, we find that CFHR5 rare variant burden significantly associates with a decreased risk of broadly defined AMD (odds ratio [OR] = 0.75, p = 7 × 10-4), with this association primarily driven by pLoF variants. Furthermore, the association of CFHR5 rare variants with AMD protection is estimated to be stronger for individuals with the CFH rs1061170 AMD risk allele (p.Tyr402His [p.Y402H]; interaction p = 0.04). Corresponding analyses of strict AMD were underpowered. However, we observe that thinning of the photoreceptor layer outer segment strongly predicts strict AMD and find that CFHR5 rare variant burden is significantly associated with increased thickness of this retinal layer (+0.34 SD, p = 4 × 10-4, n = 45,365). These findings suggest CFHR5 inhibition as a potential therapeutic approach for AMD.

Age-related macular degeneration (AMD) is a progressive disorder and the leading cause of central vision loss. Age is the most important risk factor, followed by genetics and smoking. However, ageing is a complex process, and biological age can deviate from chronological age between individuals and within different organ systems. Initially, we used machine learning to predict the biological age of the immune, cardiovascular, pulmonary, renal, musculoskeletal, metabolic and hepatic systems by analysing various physiological and physical markers in the UK Biobank cohort. Then, we investigated the association of each organ's biological age with incident AMD derived from electronic health record data as well as with different AMD genetic risk scores. We observed that most organ systems in participants who developed AMD after recruitment showed accelerated ageing compared with controls, with the immune system being the most affected, especially in younger males. Surprisingly, we found that AMD patients showed slower ageing of their hepatic system compared to controls, particularly in female patients. The overall AMD genetic risk score was associated with faster organ ageing across all tissues except cardiovascular and pulmonary, while genetic risk scores stratified by pathways differently influenced each organ system. In conclusion, we found differential organ ageing associated with AMD. Significantly, genetic risk variants of AMD are associated with differential ageing of various organ systems.

Clinicians recognize the heterogeneity of age-related macular degeneration (AMD) in presentation, progression, and treatment response, as well as the challenges in distinguishing it from other macular degenerations. As part of the 2024 Ryan Initiative for Macular Research meeting, a group of clinician-scientists and basic scientists were convened to consider the question of whether AMD should be classified as a single disorder or a spectrum of conditions. To answer this question, we reviewed research on several "dimensions" that constitute AMD risk or pathogenesis: genetics, ancestry, retinal imaging findings, diet and environment, aging, and outer retinal molecular and cellular pathways. The group reached a consensus that AMD represents a heterogeneous collection of disease states arising from the interplay of these dimensions. This heterogeneity can be conceived of as a "cloud" of AMD phenotypes. Defining subtypes within this "cloud" requires longitudinal cohorts of well-genotyped and phenotyped patients who progress from no AMD through late AMD, analyzed by unsupervised learning. Comparing the AMD subtypes that emerge from this analysis, especially -omics data from each subtype, will illuminate biology that is applicable to certain subtypes of AMD patients and molecular pathogenic mechanisms that universally apply to all AMD. This knowledge will, in turn, drive improved drug development.

To describe clinical characteristics of polypoidal choroidal vasculopathy (PCV) in a large Caucasian cohort.

Multicenter retrospective cohort study in 3 tertiary referral centers in the Netherlands.

Caucasian patients with an indocyanine green angiography-confirmed diagnosis of PCV in one or both eyes.

The medical charts and multimodal imaging (MMI) of the included patients were assessed retrospectively by 2 independent assessors. Any discrepancies between graders were resolved by a senior retinal specialist. A predefined set of phenotypic characteristics were graded on MMI, including optical coherence tomography, color fundus photography, fundus fluorescein angiography, and indocyanine green angiography.

PCV patients were distributed among 4 phenotypically different types, based on a previously published description: PCV-AMD: PCV with drusenoid age-related macular degeneration (AMD; type A); PCV-BNN: PCV without drusen but with a branching neovascular network (BNN; type B); PCV-i: isolated PCV without drusen or a BNN (type C); PCV-CSC: PCV with a background of central serous chorioretinopathy (CSC; type D).

We included 332 eyes of 305 PCV patients, with 179 out of 305 patients being female (58.7%). The average age at diagnosis was 73 years. The included eyes had the following types: PCV-AMD in 188 eyes (58.4%); PCV-BNN in 61 eyes (18.9%); PCV-i in 15 eyes (4.7%); PCV-CSC in 58 eyes (18.0%). Patients with PCV-AMD were older and more often female than patients with PCV-CSC. The median best-corrected visual acuity of affected eyes was 0.30 logMAR (interquartile range: 0.10 - 0.52), with a large range in each type. A median of 2 polypoidal lesions per eye was found (range: 1 - 12), with no significant differences between types. The choroidal thickness beneath the fovea and beneath polypoidal lesions was significantly higher in PCV-CSC than in PCV-AMD (both p<0.001).

PCV in Caucasian patients comprises a spectrum of different phenotypes: it may present with signs of drusenoid AMD, with a background of CSC, or without signs of either diseases. We found a different phenotype distribution when compared to published findings in Asian patients with PCV.

Genetic disorders impacting vision affect millions of individuals worldwide, including age-related macular degeneration (common) and inherited retinal disorders (rare). There is incomplete understanding of the impact of genetic variation on gene expression in the human retina, and its role in genetic disorders. Through the generation of whole genome sequencing and bulk RNA-sequencing of neurosensory retina (NSR) and retinal pigment epithelium (RPE) from 201 post-mortem eyes, we uncovered common and rare genetic variants shaping retinal expression profiles. This includes 1,483,595 significant cis-expression quantitative trait loci (eQTLs) impacting 9,959 and 3,699 genes in NSR and RPE, respectively, with associated genetic variants enriched to cis-candidate regulatory elements and notable shared eGenes between NSR and RPE. We also detected 1051 expression outliers and prioritised 299 rare non-coding single-nucleotide, structural variants or copy number variants as plausible drivers for 28% of outlier events. This study increases understanding of gene expression regulation in the human retina.

AMD is a multifactorial progressive disease of the central retina that leads to severe vision loss among the elderly. Genome-wide association studies in AMD patients and preclinical data have identified a dysregulated complement system and aberrant microglia responses in the pathogenesis of AMD. Specifically, a genetic variant in the complement factor H (CFH) gene, an important inhibitor of the alternative complement pathway, confers the strongest risk for AMD. Here, we investigated whether moss-derived recombinant human CFH proteins, termed CPV-101 and CPV-104, can modulate microglia reactivity and limit retinal degeneration in a murine light damage paradigm mimicking important features of AMD.

Two glycosylated human recombinant CFH proteins CPV101, and CPV-104 were produced in moss suspension cultures. In addition, glycans of the CPV-104 variant are sialylated, an optimization that makes CPV-104 an analog of human CFH. BALB/cJ mice received intravitreal injections of 5 µg CPV-101 and CPV-104 or vehicle, starting 1 day prior to exposure to 10,000 lx white light for 30 min. The effects of CPV-101 and CPV-104 treatment on mononuclear phagocyte and Müller cell reactivity were analyzed by immunostainings of retinal sections and flat mounts. Gene expression of microglia markers was analyzed using quantitative real-time PCR (qRT-PCR). Optical coherence tomography (OCT); Blue Peak Autofluorescence (BAF); terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and morphometric analyses were used to quantify the extent of retinal degeneration and photoreceptor apoptosis.

Light-exposed mice treated with moss-derived recombinant human full-length CFH showed reduced complement activation and MAC deposition in the retina. Concomitantly, mononuclear phagocyte and Müller cell reactivity in light-exposed retinas were also ameliorated upon CFH substitution. Moreover, attenuated light-induced retinal degeneration was detected in mice that received moss-derived CFH.

Modulating the alternative complement pathway using moss-derived recombinant human full-length CFH variant CPV-101 and CPV-104 counter-regulate gliosis and attenuates light-induced retinal degeneration, highlighting a promising concept for the treatment of AMD patients.

Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that plays a crucial role in maintaining extracellular matrix integrity. Studies suggest that AAT augmentation therapy may benefit multiple eye diseases, including age-related macular degeneration (AMD). However, the function of endogenous AAT in the eye remains unclear. Here we used genetic knockout mice to study the role of AAT in eye health. We show that loss of AAT results in Bruch's membrane (BrM) thickening driven in part by increased laminin deposition with a concomitant decrease in collagen and elastin, which are two other critical BrM components. Interestingly, BrM remodeling due to excess extracellular protease activity reduced the age-related deposition at the BrM of apolipoprotein E, while increasing complement factor H and lowering secretion of the proangiogenic vascular endothelial growth factor. Despite these changes, the phagocytic function of the retinal pigment epithelium was not affected nor was the expression of genes that partake in photoreceptor cell metabolism. Consistent with loss of AAT resulting in changes that should alleviate AMD pathologies, human AMD donor eyes exhibited lower AAT expression levels in the BrM/choroid layer when compared to healthy donor eyes. Together, the study provides insight into AAT's function and its potential involvement in AMD.

Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration worldwide. It is characterized by the sequential death of rod and cone photoreceptors, the cells responsible for night and daylight vision, respectively. Although the expression of most RP genes occurs only in rods, there is a secondary degeneration of cones. One possible mechanism of cone death is metabolic dysregulation. Photoreceptors are highly metabolically active, consuming large quantities of glucose and producing substantial amounts of lactate. The retinal pigment epithelium (RPE) mediates the transport of glucose from the blood to photoreceptors and, in turn, removes lactate, which can influence the rate of consumption of glucose by the RPE. One model for metabolic dysregulation in RP suggests that following the death of rods, lactate levels are substantially diminished causing the RPE to withhold glucose, resulting in nutrient deprivation for cones. Here, we present adeno-associated viral vector-mediated delivery of monocarboxylate transporter 2 (MCT2, Slc16a7) into the eye, with expression limited to RPE cells, with the aim of promoting lactate uptake from the blood and encouraging the passage of glucose to cones. We demonstrate prolonged survival and function of cones in rat and mouse RP models, revealing a possible gene-agnostic therapy for preserving vision in RP. We also present the use of fluorescence lifetime imaging-based biosensors for lactate and glucose within the eye. Using this technology, we show changes to lactate and glucose levels within MCT2-expressing RPE, suggesting that cone survival is impacted by changes in RPE metabolism.

Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide, characterized by the accumulation of extracellular drusen deposits within the macula. The pathogenesis of AMD is multifactorial, involving oxidative stress, chronic inflammation, immune system dysregulation, and genetic predisposition. A key contributor to disease progression is the excessive accumulation of reactive oxygen species (ROS), which damage retinal pigment epithelium (RPE) cells and disrupt cellular homeostasis. Additionally, immunosenescence and chronic low-grade inflammation exacerbate AMD pathology, further impairing retinal integrity. Despite ongoing research, effective therapeutic options remain limited, and there is no definitive cure for AMD. This review explores the intricate molecular mechanisms underlying AMD, including the role of oxidative stress, chronic inflammation, and genetic factors in RPE dysfunction. Furthermore, we highlight potential therapeutic strategies targeting these pathways, as well as the emerging role of bioinformatics and artificial intelligence in AMD diagnosis and treatment development. By improving our understanding of AMD pathophysiology, we can advance the search for novel therapeutic interventions and preventative strategies.

To evaluate the relationship between the presence of reticular pseudodrusen (RPD) and the risk allele of ARMS2 rs10490924 variation in dry-AMD patients by using multimodal imaging. Also, to compare patients with and without RPD and healthy volunteers according to the distribution of the risk allele.

In this cross-sectional study, dry-AMD patients with (Group A, n = 50) and without (Group B, n = 50) RPD and healthy volunteers (Group C, n = 50) were enrolled. After detailed ophthalmologic examination, confocal scanning laser ophthalmoscope (Heidelberg, Germany) was used to acquire near infra-red (NIR) imaging for RPD and the diagnosis was confirmed by Spectral Domain-Optical coherence tomography (Heidelberg, Germany). In silent choroidal neovascularization suspicion, optical coherence tomography angiography (Optovue, Fremont, CA) was performed and those were excluded. For genetic assessment, peripheric blood sampling was performed. Using next-generation sequencing technique (NGS), ARMS2 rs10490924 single nucleotide polymorphism was investigated. Groups were compared according to the distribution of the risky allele.

150 eyes of 150 participants were included. In Group A, 42% (21) of patients were heterozygous for the T risk allele, 30% (15) were homozygous, and the risk allele was not detected in 28% (14). In Group B, 44% (22) of patients were heterozygous, 17% (8) were homozygous, and the risk allele was not detected in 39% (20). In Group C, 30% (15) of participants were heterozygous, 4% (2) were homozygous, and variation was not observed in 64% (32). Homozygous participants in Group A were significantly higher than other two groups (Group A-B: OR = 2.67, 95% CI: 0.895, 8.020; Group A-C: OR = 17.14, 95% CI: 3.449, 85.208) while in Group B, homozygous individuals were higher than Group C (respectively, p values 0.0039, 0.0002, 0.013). T risky allele frequencies were 51%, 38%, and 20% in Groups A, B, and C, respectively, which was significantly higher in Group A (p = 0.02).

Genetic influence in AMD is inevitable while certain differences according to different ethnicities may apply. Association of genetic variations and imaging findings like RPD is lacking among literature for different populations. By the aspect of this study, the relationship between RPD and ARMS2 rs10490924 polymorphism in dry-AMD patients were highlighted among Turkish population by using multimodal imaging for the first time.

What is Known? Pathophysiology of age-related macular degeneration is influenced from multiple factors including single nucleotide polymorphisms. The variations of ARMS2 are suspected well in the current literature. Reticular pseudodrusen is related to advanced stages of age related macular degeneration disease. What is New? The ARMS2 rs10490924 risk genotype is associated with the presence of reticular pseudodrusen in dry age related macular degeneration patients. Homozygous genotype of T risk allele is evaluated significantly higher in dry age related macular degeneration patients with reticular pseudodrusen.

Age-related macular degeneration (AMD) is a leading cause of visual impairment with the risk of developing the disease influenced by a combination of genetic and environmental factors. With the recent expansion of treatment options, enhancing diagnostic accuracy and improving access to treatment are increasingly becoming the focus of interest. By using data from genome-wide association studies (GWAS) to generate polygenic risk scores (PRS), an assessment of an individual's genetic risk for AMD is feasible. While the predictive accuracy of the AMD-PRS is most robust for individuals at very high genetic risk, genetic diagnostic testing is warranted due to the large number of affected individuals resulting from the high prevalence of AMD. Early genetic confirmation of AMD-related pathology can facilitate timely treatment initiation, potentially improving patient outcomes.

Age-related macular degeneration (AMD) and age-related neurological diseases (ANDs), such as Alzheimer's and Parkinson's Diseases, are increasingly prevalent conditions that significantly contribute to global morbidity, disability, and mortality. The retina, as an accessible part of the central nervous system (CNS), provides a unique window to study brain aging and neurodegeneration. By examining the associations between AMD and ANDs, this review aims to highlight novel insights into fundamental mechanisms of aging and their role in neurodegenerative disease progression. This review integrates knowledge from the emerging field of aging research, which identifies common denominators of biological aging, specifically loss of proteostasis, impaired macroautophagy, mitochondrial dysfunction, and inflammation. Finally, we emphasize the clinical relevance of these pathways and the potential for cross-disease therapies that target common aging hallmarks. Identifying these shared pathways could open avenues to develop therapeutic strategies targeting mechanisms common to multiple degenerative diseases, potentially attenuating disease progression and promoting the healthspan.

To identify the susceptibility loci for myopic macular neovascularization (mMNV) in patients with high myopia.

A genome-wide association study (GWAS) meta-analysis (meta-GWAS).

We included 2783 highly myopic individuals, including 608 patients with mMNV and 2175 control participants without mMNV.

We performed a meta-analysis of 3 independent GWASs conducted according to the genotyping platform (Illumina Asian Screening Array [ASA] data set, Illumina Human610 BeadChip [610K] data set, and whole genome sequencing [WGS] data set), adjusted for age, sex, axial length, and the first to third principal components. We used DeltaSVM to evaluate the binding affinity of transcription factors (TFs) to DNA sequences around the susceptibility of single nucleotide polymorphisms (SNPs). In addition, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci.

The association between SNPs and mMNV in patients with high myopia.

The meta-GWAS identified rs56257842 at TEX29- LINC02337 as a novel susceptibility SNP for mMNV (odds ratio [OR]meta = 0.62, Pmeta = 4.63 × 10-8, I2 = 0.00), which was consistently associated with mMNV in all data sets (ORASA = 0.59, PASA = 1.71 × 10-4; OR610K = 0.63, P610K = 5.53 × 10-4; ORWGS = 0.66, PWGS = 4.38 × 10-2). Transcription factor-wide analysis showed that the TFs ZNF740 and EGR1 lost their binding affinity to this locus when rs56257842 had the C allele (alternative allele), and the WNT signaling-related TF ZBTB33 gained binding affinity when rs56257842 had the C allele. When we examined the associations of AMD susceptibility loci, rs12720922 at CETP showed a statistically significant association with mMNV (ORmeta = 0.52, Pmeta = 1.55 × 10-5), whereas rs61871745 near ARMS2 showed a marginal association (ORmeta = 1.25, Pmeta = 7.79 × 10-3).

Our study identified a novel locus associated with mMNV in high myopia. Subsequent analyses offered important insights into the molecular biology of mMNV, providing the potential therapeutic targets for mMNV. Furthermore, our findings imply shared genetic susceptibility between mMNV and AMD.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Genome-wide association studies of lipid species have identified several loci shared with various diseases, however, the relationship between lipid species and disease risk remains poorly understood. Here we investigated whether the plasma levels of lipid species are causally linked to disease risk.

We built genetic predictors of 179 lipid species, measured in 7174 Finnish individuals, by utilising either 11 high-impact genomic loci or genome-wide polygenic scores (PGS). We assessed the impact of the lipid species on seven diseases by performing disease association across FinnGen (n = 500,348), UK Biobank (n = 420,531), and Generation Scotland (n = 20,032). We performed univariable Mendelian randomisation (MR) and multivariable MR (MVMR) analyses to examine whether lipid species impact disease risk independently of standard lipids.

PGS explained >4% of the variance for 34 lipid species but variants outside the high-impact loci had only a marginal contribution. Variants within the high-impact loci showed association with all seven diseases. MVMR supported a causal role of ApoB in ischaemic heart disease after accounting for lipid species. Phosphatidylethanolamine-increasing LIPC variants seemed to lower age-related macular degeneration risk independently of HDL-cholesterol. MVMR suggested a protective effect of four lipid species containing arachidonic acid on cholelithiasis risk independently of Total Cholesterol.

Our study demonstrates how genetic predictors of lipid species can be utilised to gain insights into disease risk. We report potential links between lipid species and age-related macular degeneration and cholelithiasis risk, which can be explored for their utility in disease risk prediction and therapy.

The funders had no role in the study design, data analyses, interpretation, or writing of this article.

Age-related macular degeneration (AMD) is a leading cause of vision loss worldwide. Genome-wide association studies (GWAS) of AMD have identified dozens of risk loci that may house disease targets. However, variants at these loci are largely noncoding, making it difficult to assess their function and whether they are causal. Here, we present a single-cell gene expression and chromatin accessibility atlas of human retinal pigment epithelium (RPE) and choroid to systematically analyze both coding and noncoding variants implicated in AMD. We employ HiChIP and Activity-by-Contact modeling to map enhancers in these tissues and predict cell and gene targets of risk variants. We further perform allele-specific self-transcribing active regulatory region sequencing (STARR-seq) to functionally test variant activity in RPE cells, including in the context of complement activation. Our work nominates new pathogenic variants and mechanisms in AMD and offers a rich and accessible resource for studying diseases of the RPE and choroid.