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Ueta T, Ishihara K, Notomi S, Lee J-J, Maidana DE, Efstathiou NE, Murakami Y, Hasegawa E, Azuma K, Toyono T, Paschalis EI, Aihara M, Miller JW, Vavvas DG. RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization. Proc Natl Acad Sci U S A 2019;116(47):23705-23713.Abstract
Inflammation plays an important role in pathological angiogenesis. Receptor-interacting protein 1 (RIP1) is highly expressed in inflammatory cells and is known to play an important role in the regulation of apoptosis, necroptosis, and inflammation; however, a comprehensive description of its role in angiogenesis remains elusive. Here, we show that RIP1 is abundantly expressed in infiltrating macrophages during angiogenesis, and genetic or pharmacological inhibition of RIP1 kinase activity using kinase-inactive RIP1 mice or necrostatin-1 attenuates angiogenesis in laser-induced choroidal neovascularization, Matrigel plug angiogenesis, and alkali injury-induced corneal neovascularization in mice. The inhibitory effect on angiogenesis is mediated by caspase activation through a kinase-independent function of RIP1 and RIP3. Mechanistically, infiltrating macrophages are the key target of RIP1 kinase inhibition to attenuate pathological angiogenesis. Inhibition of RIP1 kinase activity is associated with caspase activation in infiltrating macrophages and decreased expression of proangiogenic M2-like markers but not M1-like markers. Similarly, in vitro, catalytic inhibition of RIP1 down-regulates the expression of M2-like markers in interleukin-4-activated bone marrow-derived macrophages, and this effect is blocked by simultaneous caspase inhibition. Collectively, these results demonstrate a nonnecrotic function of RIP1 kinase activity and suggest that RIP1-mediated modulation of macrophage activation may be a therapeutic target of pathological angiogenesis.
of in of Consortium GGPAD (GGLAD), Hauser MA, Allingham RR, Aung T, Van Der Heide CJ, Taylor KD, Rotter JI, Wang S-HJ, Bonnemaijer PWM, Williams SE, Abdullahi SM, Abu-Amero KK, Anderson MG, Akafo S, Alhassan MB, Asimadu I, Ayyagari R, Bakayoko S, Nyamsi PB, Bowden DW, Bromley WC, Budenz DL, Carmichael TR, Challa P, Chen Y-DI, Chuka-Okosa CM, Cooke Bailey JN, Costa VP, Cruz DA, DuBiner H, Ervin JF, Feldman RM, Flamme-Wiese M, Gaasterland DE, Garnai SJ, Girkin CA, Guirou N, Guo X, Haines JL, Hammond CJ, Herndon L, Hoffmann TJ, Hulette CM, Hydara A, Igo RP, Jorgenson E, Kabwe J, Kilangalanga NJ, Kizor-Akaraiwe N, Kuchtey RW, Lamari H, Li Z, Liebmann JM, Liu Y, Loos RJF, Melo MB, Moroi SE, Msosa JM, Mullins RF, Nadkarni G, Napo A, Ng MCY, Nunes HF, Obeng-Nyarkoh E, Okeke A, Okeke S, Olaniyi O, Olawoye O, Oliveira MB, Pasquale LR, Perez-Grossmann RA, Pericak-Vance MA, Qin X, Ramsay M, Resnikoff S, Richards JE, Schimiti RB, Sim KS, Sponsel WE, Svidnicki PV, Thiadens AAHJ, Uche NJ, van Duijn CM, de Vasconcellos JPC, Wiggs JL, Zangwill LM, Risch N, Milea D, Ashaye A, Klaver CCW, Weinreb RN, Ashley Koch AE, Fingert JH, Khor CC. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry. JAMA 2019;322(17):1682-1691.Abstract
Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.
Pan P, Weisenberger DJ, Zheng S, Wolf M, Hwang DG, Rose-Nussbaumer JR, Jurkunas UV, Chan MF. Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy. Sci Rep 2019;9(1):16385.Abstract
Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal deturgescence and transparency. In Fuchs endothelial corneal dystrophy (FECD), an accelerated loss and dysfunction of endothelial cells leads to progressively severe visual impairment. An abnormal accumulation of extracellular matrix (ECM) is a distinctive hallmark of the disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully understood. Here, we investigate genome-wide and sequence-specific DNA methylation changes of miRNA genes in corneal endothelial samples from FECD patients. We discover that miRNA gene promoters are frequent targets of aberrant DNA methylation in FECD. More specifically, miR-199B is extensively hypermethylated and its mature transcript miR-199b-5p was previously found to be almost completely silenced in FECD. Furthermore, we find that miR-199b-5p directly and negatively regulates Snai1 and ZEB1, two zinc finger transcription factors that lead to increased ECM deposition in FECD. Taken together, these findings suggest a novel epigenetic regulatory mechanism of matrix protein production by corneal endothelial cells in which miR-199B hypermethylation leads to miR-199b-5p downregulation and thereby the increased expression of its target genes, including Snai1 and ZEB1. Our results support miR-199b-5p as a potential therapeutic target to prevent or slow down the progression of FECD disease.
Testi I, Agrawal R, Mahajan S, Agarwal A, Gunasekeran DV, Raje D, Aggarwal K, Murthy SI, Westcott M, Chee SP, McCluskey P, Ho SL, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Carreño E, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Esposti SD, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Singh R, Sharma A, Sharma K, Zierhut M, Rousselot A, Grant R, Kon OM, Cunningham ET, Kempen J, Nguyen QD, Pavesio C, Gupta V. Tubercular Uveitis: Nuggets from Collaborative Ocular Tuberculosis Study (COTS)-1. Ocul Immunol Inflamm 2019;:1-9.Abstract
Tuberculosis (TB) is a major infection that can affect the eye as first and sole presentation without features of systemic disease. Controversy exists regarding diagnosis and management of tubercular uveitis (TBU), further compounded by regional variations in disease expression. Collaborative Ocular Tuberculosis Study (COTS)-1 aims to address knowledge deficits through collaboration amongst uveitis specialists across the globe by sharing the data of patients with TBU presented at participating centers from January 2004 to December 2014. Data collection was facilitated by a novel method of real-time encrypted web-based data entry allowing regular updates as new data and recommendations become available. Information on clinical features, investigation findings, management, and treatment outcomes were reviewed to get an idea about real world scenario. The current review aims to focus on methodology and briefing of published reports from COTS group in COTS-1 study to highlight key messages from this large data.
Muqit MMK, Kourgialis N, Jackson-deGraffenried M, Talukder Z, Khetran ER, Rahman A, Chan WO, Chowdury FA, Nag D, Ahmad J, Friedman DS. Trends in Diabetic Retinopathy, Visual Acuity, and Treatment Outcomes for Patients Living With Diabetes in a Fundus Photograph-Based Diabetic Retinopathy Screening Program in Bangladesh. JAMA Netw Open 2019;2(11):e1916285.Abstract
Importance: Diabetic retinopathy (DR) is the leading cause of low vision among working-age adults. An estimated 6.9 million people in Bangladesh were living with diabetes in 2017, which is projected to increase to more than 10 million people in 2025. Currently, no standardized and/or large-scale DR screening program exists in Bangladesh. Objective: To develop a novel fundus photograph-based eye screening model for early detection of DR to prevent vision loss in Bangladeshi individuals with diabetes. Design, Setting, and Participants: In this cross-sectional study, 49 264 patients with diabetes underwent opportunistic eye screening at 2 eye hospitals and 1 diabetic hospital in Bangladesh between June 1, 2010, and September 30, 2017. The data set was analyzed from April 8 to December 30, 2018. Technicians were trained to obtain 2-field digital fundus photographs and to grade each according to a standardized DR severity scale. Each patient was counseled and triaged for treatment using defined DR referral criteria. Main Outcomes and Measures: Primary DR grading outcomes, visual acuity, and treatment outcomes. Results: A total of 49 264 patients (54.3% male; mean [SD] age, 50.8 [12.3] years) underwent DR screening during a 7-year period. The DR prevalence rate across all 3 sites was 33% (95% CI, 33%-33%). Prevalence rates varied by center (Chittagong, 64.6% [95% CI, 64.0%-65.0%]; Dhaka, 39.8% [95% CI, 39.0%-41.0%]; and Feni, 13.0% [95% CI, 13.0%-14.0%]). Across all age groups, male patients were at higher risk of prevalent DR than female patients (odds ratio, 1.99; 95% CI, 1.90-2.07). The prevalence was 3.9% for preproliferative DR, 7.8% for proliferative DR, and 19.2% for maculopathy. Individuals with DR had significantly worse visual acuity than those with no DR (best-corrected visual acuity, 0.35 vs 0.21 logMAR; P < .001). The rate of moderate visual impairment was 12.2%, and the rate of blindness was 2.5%. Primary treatments included laser photocoagulation (n = 1637), intravitreal injection (n = 1440), and vitrectomy (n = 309). Conclusions and Relevance: Screening Bangladeshi individuals known to have diabetes using fundus photography identified large numbers of patients with sight-threatening proliferative DR, maculopathy, and visual impairment or blindness. Expansion of eye screening services in Bangladesh is warranted as part of a national government eye care and diabetes health policy.
Wang Y, Lin Z, Wen L, Rong SS, Ding XX, Li D, Feng KM, Wang FH, Liang YB, Zhai G. Rationale, Design, Methodology and Baseline Data of Fushun Diabetic Retinopathy Cohort Study (FS-DIRECT). Ophthalmic Epidemiol 2019;:1-10.Abstract
: To describe the rationale, design, methodology and baseline characteristics of Fushun Diabetic Retinopathy Cohort Study (FS-DIRECT), a community-based prospective cohort study in patients with type 2 diabetes mellitus (T2DM) living in northeast China.: Patients with T2DM, aged 30 years and above from communities of Fushun city, Liaoning province, China, were recruited. The presence and severity of the diabetic retinopathy (DR) were determined by a modified Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy scale of 6 fields fundus photographs. Detailed ocular examinations and questionnaires were collated, in addition to blood and urine sample collection.: Of the 2224 subjects eligible for the FS-DIRECT, 2033 (91.4%) participated in the study. The majority of participants were female (58.9%), the average age was 62.1 ± 9.1 years. The overall prevalence rates of DR, non-proliferative DR, proliferative DR, diabetic macular edema, and vision-threatening retinopathy were 44.3%, 40.0%, 4.3%, 15.2%, and 12.3%, respectively. Compared to the patients without DR, patients with DR had lower income, an earlier onset of diabetes, a longer duration of diabetes, higher proportion of insulin use, higher fasting plasma glucose, HbA1c, systolic blood pressure, total cholesterol and high density lipoprotein, as well as a higher level of urine protein (all < .05).: The baseline data of FS-DIRECT showed a high prevalence of DR in a community of northeast China. Further investigation will provide key information about the risk factors, impact, and trends of DR in this region.
Notomi S, Ishihara K, Efstathiou NE, Lee J-J, Hisatomi T, Tachibana T, Konstantinou EK, Ueta T, Murakami Y, Maidana DE, Ikeda Y, Kume S, Terasaki H, Sonoda S, Blanz J, Young L, Sakamoto T, Sonoda K-H, Saftig P, Ishibashi T, Miller JW, Kroemer G, Vavvas DG. Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina. Proc Natl Acad Sci U S A 2019;116(47):23724-23734.Abstract
The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch's membrane were reduced in knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.
Bennett CR, Bex PJ, Bauer CM, Merabet LB. The Assessment of Visual Function and Functional Vision. Semin Pediatr Neurol 2019;31:30-40.Abstract
The complete assessment of vision-related abilities should consider visual function (the performance of components of the visual system) and functional vision (visual task-related ability). Assessment methods are highly dependent upon individual characteristics (eg, the presence and type of visual impairment). Typical visual function tests assess factors such as visual acuity, contrast sensitivity, color, depth, and motion perception. These properties each represent an aspect of visual function and may impact an individual's level of functional vision. The goal of any functional vision assessment should be to measure the visual task-related ability under real-world scenarios. Recent technological advancements such as virtual reality can provide new opportunities to improve traditional vision assessments by providing novel objective and ecologically valid measurements of performance, and allowing for the investigation of their neural basis. In this review, visual function and functional vision evaluation approaches are discussed in the context of traditional and novel acquisition methods.
Neumann R, Nguyen QD, Kramer M, Zierhut M, Kempen JH, DeSmet M, Wickstrom K. ISOPT Hot Topic Panel Discussion on Uveitis and Inflammation. J Ocul Pharmacol Ther 2019;35(8):433-440.Abstract
For this "hot topic" session in uveitis we selected first and foremost an issue that puts our clinical work and research in "holding pattern." The issue is our method of evaluating the severity of uveitis. We posed the following questions to our esteemed panelists: 1.The relative significance of cells vs. flare in following uveitis patients 2.Cells/flare measurements 3.A glance into the future and the relevance of endpoints in clinical studies and their methodologies While there are different opinions in managing and monitoring uveitis patients, there seems to be an agreement on the high need of improving objective mode/s of reliably measuring both cells and flare and better understand their significance.
Yin Y, de Lima S, Gilbert H-Y, Hanovice NJ, Peterson SL, Sand R, Sergeeva EG, Wong KA, Xie L, Benowitz LI. Optic nerve regeneration: A long view. Restor Neurol Neurosci 2019;Abstract
The optic nerve conveys information about the outside world from the retina to multiple subcortical relay centers. Until recently, the optic nerve was widely believed to be incapable of re-growing if injured, with dire consequences for victims of traumatic, ischemic, or neurodegenerative diseases of this pathway. Over the past 10-20 years, research from our lab and others has made considerable progress in defining factors that normally suppress axon regeneration and the ability of retinal ganglion cells, the projection neurons of the retina, to survive after nerve injury. Here we describe research from our lab on the role of inflammation-derived growth factors, suppression of inter-cellular signals among diverse retinal cell types, and combinatorial therapies, along with related studies from other labs, that enable animals with optic nerve injury to regenerate damaged retinal axons back to the brain. These studies raise the possibility that vision might one day be restored to people with optic nerve damage.
Menon M, Mohammadi S, Davila-Velderrain J, Goods BA, Cadwell TD, Xing Y, Stemmer-Rachamimov A, Shalek AK, Love JC, Kellis M, Hafler BP. Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration. Nat Commun 2019;10(1):4902.Abstract
Genome-wide association studies (GWAS) have identified genetic variants associated with age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly. However, it has been challenging to identify the cell types associated with AMD given the genetic complexity of the disease. Here we perform massively parallel single-cell RNA sequencing (scRNA-seq) of human retinas using two independent platforms, and report the first single-cell transcriptomic atlas of the human retina. Using a multi-resolution network-based analysis, we identify all major retinal cell types, and their corresponding gene expression signatures. Heterogeneity is observed within macroglia, suggesting that human retinal glia are more diverse than previously thought. Finally, GWAS-based enrichment analysis identifies glia, vascular cells, and cone photoreceptors to be associated with the risk of AMD. These data provide a detailed analysis of the human retina, and show how scRNA-seq can provide insight into cell types involved in complex, inflammatory genetic diseases.
Asbell PA, Aquavella JV, Hamrah P, Pepose JS, Rose L, Ucakhan O. ISOPT Hot Topic Panel Discussion on Cornea Anterior Segment Disease. J Ocul Pharmacol Ther 2019;35(8):447-456.Abstract
The cornea and its adnexa pose a unique situation of a tightly defined set of requirements for its function. This includes: transparency, perfect built to obtain appropriate refractive power, protective barrier from microbial invaders. Moreso, the cornea also endures extreme external physical conditions (temperature, high and low humidity, winds and alike). All these functions are maintained while preserving a constant state of homogenous wetting. Toward that end the cornea is equipped with an elaborated network of sensory neural network. While enabling the blinking reflex and maintaining the physiological steady state of wetting, this neural network also makes the cornea prone to the discomfort that with or without associated changes seen on medical examination. ISOPT Clinical 2018 discussion touched upon this hypercomplex situation, addressing the role of inflammation and its resulting discomfort in dry eye conditions. The discussion also engulfed the emerging neuropathic pain syndrome that is recently gaining more attention. Another related topic was the utilization of autologous serum tears and its ability to provide amelioration to desperate patients. Finally, the panel discussed the issue of treating corneal infection, including when and how to utilize steroids in the course of therapy. We assume the reader will find interest in this discussion that directly addresses issues seen day in and day out in our busy clinics.

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