Age-related Macular Degeneration

Armstrong GW, Miller JB. Telemedicine for the Diagnosis and Management of Age-Related Macular Degeneration: A Review. J Clin Med 2022;11(3)Abstract
Use of ophthalmic telemedicine for patients with age-related macular degeneration (AMD) has shown remarkable advances over recent years. The recent COVID pandemic accelerated this transition since in-person evaluation of elderly patients at high risk for advanced AMD and severe vision loss were also at higher risk for complications from COVID infection. To date, ophthalmic telemedicine has been successfully used in remote retinal consultation by general ophthalmologists for AMD management, hybrid testing visits with both in-office testing and remote evaluation, as well as early successes in home-based remote monitoring of patients with high-risk AMD. We therefore review the current literature and evidence base related to ophthalmic telemedicine for AMD.
Awh CC, Lane AM, Hawken S, Zanke B, Kim IK. Author reply: To PMID 23972322. Ophthalmology 2014;121(8):e39.
Bontzos G, Bagheri S, Ioanidi L, Kim I, Datseris I, Gragoudas E, Kabanarou S, Miller J, Tsilimbaris M, Vavvas DG. Nonresponders to Ranibizumab Anti-VEGF Treatment Are Actually Short-term Responders: A Prospective Spectral-Domain OCT Study. Ophthalmol Retina 2020;4(12):1138-1145.Abstract
PURPOSE: To investigate the inter-individual variability in duration of anti-vascular endothelial growth factor (VEGF) treatment effect in neovascular age-related macular degeneration (nvAMD). DESIGN: Prospective observational multi-centered study. PARTICIPANTS: Forty-eight patients with nvAMD treated with anti-VEGF injections were included. Both treatment naive (n=25) as well as patients who had previously received treatment with ranibizumab (n=23) more than one month prior to their enrollment were recruited. METHODS: Patients received injection with ranibizumab (0.5 mg/0.05 ml) and were followed weekly for 4 weeks with spectral-domain OCT (SD-OCT) assessing the time to maximal reduction of central retinal thickness (CRT) and the presence of intraretinal and subretinal fluid. Other data collected included age, gender, visual acuity, axial length, lens status, and previous injections. The Shapiro-Wilk test was used to examine normal distributions for all variables. Correlations were examined by calculating Spearman's correlation coeficient. Distributions of quantitative variables are described as means (±SD). Qualitative variables are summarized by counts and percentage. MAIN OUTCOME MEASURES: Time to maximal reduction of CRT and intra- and subretinal fluid after ranibizumab injection. RESULTS: A total of 48 eyes of 48 patients (age 74.8±8.3 years, 62.5% female, 52% treatment naive, 35.4% pseudophakic) were assessed. Two-thirds (64.6%) reached maximal CRT reduction earlier than the standard 4-week interval: 6.3% at 1 week postinjection, 22.9% at 2 weeks postinjection, and 35.4% at 3 weeks postinjection. Only 35.4% of patients had maximal CRT reduction at 4 weeks. Twenty percent of treatment-naive and 34.8% of non-naive patients had a week-4 CRT that was >35 μm thicker than the earlier occuring lowest CRT value (nadir). The time to maximal CRT reduction was not related to axial length, age, lens status, or history of injections. CONCLUSIONS: Optimal dosing interval for maximal CRT reduction may be less than 4 weeks for a significant proportion of patients. Most patients will be classified as complete responders if intervals less than 4 weeks are used to assess anti-VEGF treatment response. Disease load rather than eye size appears to be the driver of anti-VEGF treatment duration and therefore, dosing interval needs to be optimized in the cohort of short-term responders.
Bowers AR, Sheldon SS, DeCarlo DK, Peli E. Bioptic Telescope Use and Driving Patterns of Drivers with Age-Related Macular Degeneration. Transl Vis Sci Technol 2016;5(5):5.Abstract

PURPOSE: To investigate the telescope use and driving patterns of bioptic drivers with age-related macular degeneration (AMD). METHODS: A questionnaire addressing telescope use and driving patterns was administered by telephone interview to three groups of bioptic drivers: AMD (n = 31; median 76 years); non-AMD first licensed with a bioptic (n = 38; 53 years); and non-AMD first licensed without a bioptic (n = 47; 37 years). Driving patterns of bioptic AMD drivers were also compared with those of normal vision (NV) drivers (n = 36; 74 years) and nonbioptic AMD drivers (n = 34; 79 years). RESULTS: Bioptic usage patterns of AMD drivers did not differ from those of the younger bioptic drivers and greater visual difficulty without the bioptic was strongly correlated with greater bioptic helpfulness. Bioptic AMD drivers were more likely to report avoidance of night driving than the age-similar NV drivers (P = 0.06). However, they reported less difficulty than the nonbioptic AMD drivers in all driving situations (P ≤ 0.02). Weekly mileages of bioptic AMD drivers were lower than those of the younger bioptic drivers (P < 0.001), but not the NV group (P = 0.54), and were higher than those of the nonbioptic AMD group (P < 0.001). CONCLUSIONS: Our results suggest that bioptic telescopes met the visual demands of drivers with AMD and that those drivers had relatively unrestricted driving habits. TRANSLATIONAL RELEVANCE: Licensure with a bioptic telescope may prolong driving of older adults with AMD; however, objective measures of bioptic use, driving performance, and safety are needed.

Chee Yee C, Papakostas TD, Vavvas DG. Quantitative assessment of central retinal thickness in recurrent neovascular age-related macular degeneration. Br J Ophthalmol 2014;98(9):1308.
Chen J, Smith LEH. Altered cholesterol homeostasis in aged macrophages linked to neovascular macular degeneration. Cell Metab 2013;17(4):471-2.Abstract
Abnormal lipid metabolism has been linked to age-related macular degeneration (AMD); choroidal neovascularization in late AMD commonly causes blindness. Sene et al. (2013) now demonstrate that in aged macrophages decreased ABCA1 expression, regulated by liver X receptor and miR-33, impairs export of intracellular cholesterol, which promotes neovascular AMD.
Chen J, Smith LEH. Protective inflammasome activation in AMD. Nat Med 2012;18(5):658-60.Abstract
Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. AMD progression is associated with alterations in inflammatory pathways and the immune system. A new study identifies a protective role for inflammasomes in AMD, suggesting that inflammasome activation might be manipulated as a potential therapeutic strategy for this condition (pages 791-798).
Cho H, Pillai P, Nicholson L, Sobrin L. Inflammatory Papillitis in Uveitis: Response to Treatment and Use of Optic Nerve Optical Coherence Tomography for Monitoring. Ocul Immunol Inflamm 2016;24(2):194-206.Abstract

PURPOSE: To describe the clinical course of uveitis-associated inflammatory papillitis and evaluate the utility and reproducibility of optic nerve spectral domain optical coherence tomography (SD-OCT). METHODS: Data on 22 eyes of 14 patients with uveitis-related papillitis and optic nerve imaging were reviewed. SD-OCT measure reproducibility was determined and parameters were compared in active vs. inactive uveitis. RESULTS: Papillitis resolution lagged behind uveitis resolution in three patients. For SD-OCT measures, the intraclass correlation coefficients were 99.1-100% and 86.9-100% for intraobserver and interobserver reproducibility, respectively. All SD-OCT optic nerve measures except inferior and nasal peripapillary retinal thicknesses were significantly higher in active vs. inactive uveitis after correction for multiple hypotheses testing. Mean optic nerve central thickness decreased from 545.1 to 362.9 µm (p = 0.01). CONCLUSIONS: Resolution of inflammatory papillitis can lag behind resolution of uveitis. SD-OCT assessment of papillitis is reproducible and correlates with presence vs. resolution of uveitis.

Claessens D, Ichhpujani P, Singh RB. MacuFix® versus Amsler grid for metamorphopsia categorization for macular diseases. Int Ophthalmol 2022;42(1):229-238.Abstract
PURPOSE: Macular diseases often lead to metamorphopsia, which is traditionally tested using the Amsler grid. This study evaluates a novel method for assessing metamorphopsia, based on the software AMD-A Metamorphopsia Detector, application MacuFix®. METHODS: In this observational study, the usability of a new smartphone-based testing method to assess metamorphopsia was evaluated in 45 patients experiencing metamorphopsia in at least one eye using the questionnaire "System Usability Score (SUS)." Additionally, the diagnostic adherence of self-monitoring with the Amsler grid was compared to self-monitoring with the novel software MacuFix®. RESULTS: The average score of the SUS questionnaire in this study was 76.7 ± 15.5, corresponding to the "good" score on the grading scale. The average interval between two home administered tests was significantly shorter (6 days) when the application was used as compared to using the Amsler grid (19 days). The odds ratio of the frequency of patients using the application to the patients using the home test was 4. CONCLUSION: MacuFix® application can help in effective home monitoring of macular function as high user satisfaction and increased testing frequency was observed in its use in patients with macular diseases.
Deangelis MM, Owen LA, Morrison MA, Morgan DJ, Li M, Shakoor A, Vitale A, Iyengar S, Stambolian D, Kim IK, Farrer LA. Genetics of age-related macular degeneration (AMD). Hum Mol Genet 2017;26(R2):R246.
Dedania VS, Grob S, Zhang K, Bakri SJ. Pharmacogenomics of response to anti-VEGF therapy in exudative age-related macular degeneration. Retina 2015;35(3):381-91.Abstract

PURPOSE: To determine whether there is an association between response to intravitreal anti-vascular endothelial growth factor agents and genotype in patients with neovascular age-related macular degeneration. METHODS: Analysis of the current literature evaluating pharmacogenetics of treatment response in patients with neovascular age-related macular degeneration. RESULTS: Studies have demonstrated associations between various genotypes and response to intravitreal anti-vascular endothelial growth factor agents. Lower-risk genotypes of the CFH, ARMS2, HTRA1, and VEGF-A genes may be associated with improved visual outcomes. Additionally, frequency of injections may be associated with certain genotypes. CONCLUSION: Genetic background may influence an individual's response to treatment of neovascular age-related macular degeneration. Further studies to investigate biologic pathways of neovascular age-related macular degeneration and gene products that are directly involved might lead to better understanding of contribution of various genes to treatment response.

Deffler RA, Xu J, Bittner AK, Bowers AR, Hassan SE, Ross N, Cooley S-SL, Doubt A, Davidorf FH, Dougherty BE, Dougherty BE. Use and Perceptions of Advanced Driver Assistance Systems by Older Drivers With and Without Age-Related Macular Degeneration. Transl Vis Sci Technol 2022;11(3):22.Abstract
Purpose: Advanced driver assistance systems (ADAS) have been reported to improve the safety of elderly and normally sighted drivers. The purpose of this study was to assess exposure to, perceived safety of, comfort level with, and interest in using ADAS among drivers with age-related macular degeneration (AMD). Methods: Current drivers aged 60+ years were recruited at four US sites to complete a survey about ADAS and driving habits. Frequency of use and/or perceptions of eight ADAS were investigated. An avoidance score was generated using questions about difficult driving situations. Results: The survey was completed by 166 participants (80 with AMD vs. 86 without). Participants with AMD had worse self-rated vision than those without (34% vs. 2% poor or fair rating), and drove fewer weekly miles (median [interquartile range [IQR] 30 [15 to 75] vs. 60 [30 to 121] miles, P = 0.002). Participants with AMD reported more avoidance of difficult driving situations (P < 0.001). There was no difference in the number of ADAS used by AMD status (median [IQR for AMD = 2.5 [1 to 5] vs. 3 [2 to 4] without, P = 0.87). Greater reported number of ADAS used was associated with less avoidance of difficult situations (P = 0.02). The majority perceived improved safety with most ADAS. Conclusions: Many drivers with AMD utilize common ADAS, which subjectively improve their road safety and may help to reduce self-imposed restrictions for difficult situations and mileage. Translational Relevance: Drivers with AMD are adopting readily available ADAS, for which they reported potential benefits, such as safety and less restrictive driving.
Dib B, Lin H, Maidana DE, Tian B, Miller JB, Bouzika P, Miller JW, Vavvas DG. Mitochondrial DNA has a pro-inflammatory role in AMD. Biochim Biophys Acta 2015;1853(11 Pt A):2897-906.Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly of industrialized nations, and there is increasing evidence to support a role for chronic inflammation in its pathogenesis. Mitochondrial DNA (mtDNA) has been recently reported to be pro-inflammatory in various diseases such as Alzheimer's and heart failure. Here, we report that intracellular mtDNA induces ARPE-19 cells to secrete inflammatory cytokines IL-6 and IL-8, which have been consistently associated with AMD onset and progression. The induction was dependent on the size of mtDNA, but not on specific sequence. Oxidative stress plays a major role in the development of AMD, and our findings indicate that mtDNA induces IL-6 and IL-8 more potently when oxidized. Cytokine induction was mediated by STING (Stimulator of Interferon Genes) and NF-κB as evidenced by abrogation of the cytokine response with the use of specific inhibitors (siRNA and BAY 11-7082, respectively). Finally, mtDNA primed the NLRP3 inflammasome. This study contributes to our understanding of the potential pro-inflammatory role of mtDNA in the pathogenesis of AMD.

Douglas VP, Douglas KA, Vavvas DG, Miller JW, Miller JB. Short- and Long-Term Visual Outcomes in Patients Receiving Intravitreal Injections: The Impact of the Coronavirus 2019 Disease (COVID-19)-Related Lockdown. J Clin Med 2022;11(8)Abstract
Purpose: To investigate the short- and long-term impact of COVID-19-related lockdown on the vision of patients requiring intravitreal injections (IVI) for neovascular Age-related Macular degeneration (nvAMD), diabetic retinopathy (DR), central retinal vein occlusion (CRVO), or branch retinal vein occlusion (BRVO). Methods: This is a retrospective study from the Retina department of three Mass Eye and Ear centers. Charts of patients age of ≥ 18 years with any of the abovementioned diagnoses who had a scheduled appointment anytime between 17 March 2020 until 18 May 2020 (lockdown period in Boston, Massachusetts) were reviewed at baseline (up to 12 weeks before the lockdown), at first available follow-up (=actual f/u) during or after the lockdown period, at 3 months, 6 months, and at last available completed appointment of 2020. Results: A total of 1001 patients met the inclusion criteria. Of those patients, 479 (47.9%) completed their intended f/u appointment, while 522 missed it (canceled and "no show"). The delay in care of those who missed it was 59.15 days [standard deviation (SD) ± 49.6]. In these patients, significant loss of vision was noted at actual f/u [Best corrected visual acuity (BCVA) in LogMAR (Logarithm of the Minimum Angle of Resolution)-mean (±SD)-completed: 0.45 (±0.46), missed: 0.53 (±0.55); p = 0.01], which was more prominent in the DR group [Visual acuity (VA) change in LogMAR-mean (±SD); completed: 0.04 (±0.28), missed: 0.18 (±0.44); p = 0.02] and CRVO [completed: -0.06 (±0.27), missed: 0.11 (±0.35); p = &lt;0.001] groups followed by nvAMD [completed: 0.006 (±0.16), missed: 0.06 (±0.27); p = 0.004] and BRVO [completed: -0.02 (±0.1), missed: 0.03 (±0.14); p = 0.02] ones. Overall, a higher percent of people who missed their intended f/u experienced vision loss of more than 15 letters at last f/u compared to those who completed it [missed vs. completed; 13.4% vs. 7.4% in nvAMD (p = 0.72), 7.8% vs. 6.3% in DR (0.84), 15.5% vs. 9.9% in CRVO (p &lt; 0.001) and 9.6% vs. 2% in BRVO (p = 0.48)]. Conclusions: Delay in care of about 8.45 weeks can lead to loss of vision in patients who receive IVI with DR and CRVO patients being more vulnerable in the short-term, whereas in the long-term, CRVO patients followed by the nvAMD patients demonstrating the least vision recovery. BRVO patients were less likely to be affected by the delay in care. Adherence to treatment is key for maintaining and improving visual outcomes in patients who require IVI.
Douglas VP, Garg I, Douglas KA, Miller JB. Subthreshold Exudative Choroidal Neovascularization (CNV): Presentation of This Uncommon Subtype and Other CNVs in Age-Related Macular Degeneration (AMD). J Clin Med 2022;11(8)Abstract
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in people over the age of 50 worldwide. Exudative or neovascular AMD is a more severe subset of AMD which is characterized by the presence of choroidal neovascularization (CNV). Recent advancements in multimodal ophthalmic imaging, including optical coherence tomography (OCT) and OCT-angiography (OCT-A), have facilitated the detection and characterization of previously undetectable neovascular lesions and have enabled a more refined classification of CNV in exudative as well as nonexudative AMD patients. Subthreshold exudative CNV is a novel subtype of exudative AMD that typically presents asymptomatically with good visual acuity and is characterized by stable persistent or intermittent subretinal fluid (SRF). This review aims to provide an overview of the clinical as well as multimodal imaging characteristics of CNV in AMD, including this new clinical phenotype, and propose effective approaches for management.
Eidet JR, Reppe S, Pasovic L, Olstad OK, Lyberg T, Khan AZ, Fostad IG, Chen DF, Utheim TP. The Silk-protein Sericin Induces Rapid Melanization of Cultured Primary Human Retinal Pigment Epithelial Cells by Activating the NF-κB Pathway. Sci Rep 2016;6:22671.Abstract

Restoration of the retinal pigment epithelial (RPE) cells to prevent further loss of vision in patients with age-related macular degeneration represents a promising novel treatment modality. Development of RPE transplants, however, requires up to 3 months of cell differentiation. We explored whether the silk protein sericin can induce maturation of primary human retinal pigment epithelial (hRPE) cells. Microarray analysis demonstrated that sericin up-regulated RPE-associated transcripts (RPE65 and CRALBP). Upstream analysis identified the NF-κB pathway as one of the top sericin-induced regulators. ELISA confirmed that sericin stimulates the main NF-κB pathway. Increased levels of RPE-associated proteins (RPE65 and the pigment melanin) in the sericin-supplemented cultures were confirmed by western blot, spectrophotometry and transmission electron microscopy. Sericin also increased cell density and reduced cell death following serum starvation in culture. Inclusion of NF-κB agonists and antagonists in the culture medium showed that activation of the NF-κB pathway appears to be necessary, but not sufficient, for sericin-induced RPE pigmentation. We conclude that sericin promotes pigmentation of cultured primary hRPE cells by activating the main NF-κB pathway. Sericin's potential role in culture protocols for rapid differentiation of hRPE cells derived from embryonic or induced pluripotent stem cells should be investigated.

Farinha CVL, Cachulo ML, Alves D, Pires I, Marques JP, Barreto P, Nunes S, Costa J, Martins A, Sobral I, Laíns I, Figueira J, Ribeiro L, Cunha-Vaz J, Silva R. Incidence of Age-Related Macular Degeneration in the Central Region of Portugal: The Coimbra Eye Study - Report 5. Ophthalmic Res 2019;:1-10.Abstract
PURPOSE: To describe the 6.5-year incidence and progression of age-related macular degeneration (AMD) in a coastal town of central Portugal. METHODS: Population-based cohort study. Participants underwent standardized interviews and ophthalmological examination. Color fundus photographs were graded according to the International Classification and Grading System for AMD and ARM. The crude and age-standardized incidence of early and late AMD was calculated, and progression was analyzed. RESULTS: The 6.5-year cumulative incidence of early AMD was 10.7%, and of late AMD it was 0.8%. The incidence of early AMD was 7.2, 13.1 and 17.7% for participants aged 55-64, 65-74 and 75-84 years (p < 0.001). The late AMD incidence was 0.3, 0.9 and 2.8% for the corresponding age groups (p = 0.003). The age-standardized incidence was 10.8% (95% CI, 10.74-10.80%) for early and 1.0% (95% CI, 1.00-1.02%) for late AMD. The incidence of both neovascular AMD and geographic atrophy was 0.4%. Progression occurred in 17.2% of patients. CONCLUSION: The early AMD incidence in a coastal town of central Portugal was found to be similar to that of major epidemiological studies of European-descent populations; however, the incidence of late AMD was lower, and further analysis on risk factors will be conducted.
Farinha C, Cachulo ML, Coimbra R, Alves D, Nunes S, Pires I, Marques JP, Costa J, Martins A, Sobral I, Barreto P, Laíns I, Figueira J, Ribeiro L, Cunha-Vaz J, Silva R. Age-Related Macular Degeneration Staging by Color Fundus Photography vs. Multimodal Imaging-Epidemiological Implications (). J Clin Med 2020;9(5)Abstract
Epidemiology of age-related macular degeneration (AMD) is based on staging systems relying on color fundus photography (CFP). We aim to compare AMD staging using CFP to multimodal imaging with optical coherence tomography (OCT), infra-red (IR), and fundus autofluorescence (FAF), in a large cohort from the Epidemiologic AMD Coimbra Eye Study. All imaging exams from the participants of this population-based study were classified by a central reading center. CFP images were graded according to the International Classification and Grading System for AMD and staged with Rotterdam classification. Afterward, CFP images were reviewed with OCT, IR, and FAF and stage update was performed if necessary. Early and late AMD prevalence was compared in a total of 1616 included subjects. In CFP-based grading, the prevalence was 14.11% for early AMD ( = 228) and 1.05% ( = 17) for late AMD, nine cases (0.56%) had neovascular AMD (nAMD) and eight (0.50%) geographic atrophy (GA). Using multimodal grading, the prevalence increased to 14.60% for early AMD ( = 236) and 1.61% ( = 26) for late AMD, with 14 cases (0.87%) of nAMD and 12 (0.74%) of GA. AMD staging was more accurate with the multimodal approach and this was especially relevant for late AMD. We propose that multimodal imaging should be adopted in the future to better estimate and compare epidemiological data in different populations.
Feng L, Ju M, Lee KYV, Mackey A, Evangelista M, Iwata D, Adamson P, Lashkari K, Foxton R, Shima D, Ng YS. A Proinflammatory Function of Toll-Like Receptor 2 in the Retinal Pigment Epithelium as a Novel Target for Reducing Choroidal Neovascularization in Age-Related Macular Degeneration. Am J Pathol 2017;187(10):2208-2221.Abstract
Current treatments for choroidal neovascularization, a major cause of blindness for patients with age-related macular degeneration, treat symptoms but not the underlying causes of the disease. Inflammation has been strongly implicated in the pathogenesis of choroidal neovascularization. We examined the inflammatory role of Toll-like receptor 2 (TLR2) in age-related macular degeneration. TLR2 was robustly expressed by the retinal pigment epithelium in mouse and human eyes, both normal and with macular degeneration/choroidal neovascularization. Nuclear localization of NF-κB, a major downstream target of TLR2 signaling, was detected in the retinal pigment epithelium of human eyes, particularly in eyes with advanced stages of age-related macular degeneration. TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model, and the combination of anti-TLR2 and antivascular endothelial growth factor receptor 2 yielded an additive therapeutic effect on both area and number of spontaneous choroidal neovascularization lesions. Finally, in primary human fetal retinal pigment epithelium cells, ligand binding to TLR2 induced robust expression of proinflammatory cytokines, and end products of lipid oxidation had a synergistic effect on TLR2 activation. Our data illustrate a functional role for TLR2 in the pathogenesis of choroidal neovascularization, likely by promoting inflammation of the retinal pigment epithelium, and validate TLR2 as a novel therapeutic target for reducing choroidal neovascularization.
Fernandez-Godino R, Garland DL, Pierce EA. A local complement response by RPE causes early-stage macular degeneration. Hum Mol Genet 2015;24(19):5555-69.Abstract

Inherited and age-related macular degenerations (AMDs) are important causes of vision loss. An early hallmark of these disorders is the formation of sub-retinal pigment epithelium (RPE) basal deposits. A role for the complement system in MDs was suggested by genetic association studies, but direct functional connections between alterations in the complement system and the pathogenesis of MD remain to be defined. We used primary RPE cells from a mouse model of inherited MD due to a p.R345W mutation in EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) to investigate the role of the RPE in early MD pathogenesis. Efemp1(R345W) RPE cells recapitulate the basal deposit formation observed in vivo by producing sub-RPE deposits in vitro. The deposits share features with basal deposits, and their formation was mediated by EFEMP1(R345W) or complement component 3a (C3a), but not by complement component 5a (C5a). Increased activation of complement appears to occur in response to an abnormal extracellular matrix (ECM), generated by the mutant EFEMP1(R345W) protein and reduced ECM turnover due to inhibition of matrix metalloproteinase 2 by EFEMP1(R345W) and C3a. Increased production of C3a also stimulated the release of cytokines such as interleukin (IL)-6 and IL-1B, which appear to have a role in deposit formation, albeit downstream of C3a. These studies provide the first direct indication that complement components produced locally by the RPE are involved in the formation of basal deposits. Furthermore, these results suggest that C3a generated by RPE is a potential therapeutic target for the treatment of EFEMP1-associated MD as well as AMD.