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      A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration

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          Abstract

          Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the developed world. While treatment is effective for the neovascular or “wet” form of AMD, no therapy is successful for the non-neovascular or “dry” form. Here we discuss the current knowledge on dry AMD pathobiology and propose future research directions that would expedite the development of new treatments. In our view, these should emphasize system biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy.

          Abstract

          No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.

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          Most cited references 94

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          Oxidative damage-induced inflammation initiates age-related macular degeneration.

          Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues and in plasma samples from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.
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            A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss

            (2001)
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              Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.

              We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.
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                Author and article information

                Contributors
                jthanda@jhmi.edu
                farrer@bu.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                26 July 2019
                26 July 2019
                2019
                : 10
                Affiliations
                [1 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Wilmer Eye Institute, , Johns Hopkins University, ; Baltimore, 21287 MD USA
                [2 ]ISNI 0000000100241216, GRID grid.189509.c, Department of Ophthalmology, , Duke University Medical Center, ; Durham, 27708 NC USA
                [3 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Translational Health Sciences (Ophthalmology), , University of Bristol, ; Bristol, BS8 1TH UK
                [4 ]ISNI 0000000121901201, GRID grid.83440.3b, University College London, Institute of Ophthalmology and the National Institute for Health Research Biomedical Research Centre, , Moorfields Eye Hospital and UCL-Institute of Ophthalmology, ; London, WC1E 6BT UK
                [5 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine, , UCLA, ; Los Angeles, 90095 CA USA
                [6 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Brain Research Institute, , UCLA, ; Los Angeles, 90095 CA USA
                [7 ]ISNI 000000041936754X, GRID grid.38142.3c, Retina Service, Massachusetts Eye and Ear, Harvard Ophthalmology AMD Center of Excellence, Department of Ophthalmology, , Harvard Medical School, ; Boston, 02114 MA USA
                [8 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Department of Ophthalmology, Institute for Ophthalmic Research, , University of Tübingen, ; Tübingen, D-72076 Germany
                [9 ]ISNI 0000 0004 1936 8796, GRID grid.430387.b, Institute of Ophthalmology and Visual Science, New Jersey Medical School, , Rutgers University, ; Newark, 07103 NJ USA
                [10 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Epidemiology, and Biostatistics, , Boston University Schools of Medicine and Public Health, ; Boston, 02118 MA USA
                Article
                11262
                10.1038/s41467-019-11262-1
                6659646
                31350409
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100006312, BrightFocus Foundation (BrightFocus);
                Funded by: FundRef https://doi.org/10.13039/100007732, American Macular Degeneration Foundation (AMDF);
                Funded by: FundRef https://doi.org/10.13039/100001818, Research to Prevent Blindness (RPB);
                Award ID: Catalyst Award
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: EY027691
                Award Recipient :
                Funded by: Wilmer-Bayer Alliance Grant, Bayer Pharmaceuticals, Inc
                Funded by: FundRef https://doi.org/10.13039/100001694, International Retinal Research Foundation (International Retinal Research Foundation, Inc.);
                Funded by: FundRef https://doi.org/10.13039/501100000833, Rosetrees Trust;
                Funded by: FundRef https://doi.org/10.13039/100010661, EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020);
                Categories
                Perspective
                Custom metadata
                © The Author(s) 2019

                Uncategorized

                biomarkers, visual system, macular degeneration, systems biology

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