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

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.

Conflict of interest statement

J.T.H.: Grant funding from Bayer Pharmaceuticals, Inc. J.W.M.: Consultant/Advisor for Genentech/Roche, Bausch+Lomb, Kalvista Pharmaceuticals, ONL Therapeutics; Grant Support from Lowy Medical Research Institute; Equity in ONL Therapeutics; Patents/Royalties from ONL Therapeutics/Mass. Eye and Ear, Valeant Pharmaceuticals/Mass. Eye and Ear. C.A.T.: Alcon royalties for surgical technologies. M.Z.: Cell Cure, Chengdu Kanghong Biotech, Coherus Biosciences, Daiichi Sankyo, Frequency Therapeutics, Healios KK, Iridex, Isarna Therapeutics, Genentech/Roche, Makindus, Novartis Pharma AG, Ophthotech, Percept Corp., Rutgers University (patent). The remaining authors declare no competing interests.

Figures

Fig. 1

Spectrum of AMD. a Fundus photograph of a normal left macula. Arrowhead points to the fovea. b Right eye with intermediate, dry AMD. Arrowhead points to a typical large druse while arrow points to RPE hyperpigmentation. c Right eye with geographic atrophy. Arrowheads outline the area of GA. d Right eye with neovascular AMD. Arrowheads outline the area of choroidal neovascularization that is partially outlined by subretinal hemorrhage

Fig. 2

Histological cross-section of a human macula. a Normal macula. b Hard drusen (*) within Bruch’s membrane. c A soft druse (*) within Bruch’s membrane. (b and c are courtesy of Philip Luthert, MBBS, UCL Institute of Ophthalmology.) d Subretinal drusenoid deposits (SDDs) between shortened photoreceptor outer segments and the RPE. Arrows highlight one of several SDDs (Courtesy of Christine Curcio, Ph.D., University of Alabama Birmingham and Project MACULA AMD Histopathology resource (http://projectmacula.cis.uab.edu/). HFL Henle fiber layer, NFL nerve fiber layer, GCL ganglion cell layer, IPL inner plexiform layer, INL inner nuclear layer, OPL outer plexiform layer, ONL outer nuclear layer, POS photoreceptor outer segment, RPE retinal pigment epithelium, BM Bruch’s membrane. Bar = 25 μm

Fig. 3

Schema of the role of lipids in drusen and subretinal drusenoid deposit formation. a In the cone-rich fovea, the high cholesterol content of cones, along with lipids derived from the circulation due to a high cholesterol diet, induces apoB100 lipoprotein formation that is basally secreted. Due to age-related Bruch’s membrane changes, lipoproteins accumulate, forming the lipid wall. In the rod-rich parafovea, reverse cholesterol transport mediated through ABCA1 releases cholesterol to apoE and apoA1, forming high-density lipoproteins for the recycling of lipids including docohexanoic acid and cholesterol to rods. b Hydroxyapatite forms around retained lipids and lipoproteins, and combined with lipoprotein oxidation, induces an inflammatory response with the accumulation of inflammatory debris, leading to basal deposit and drusen formation. In the subretinal space, dysfunction of reverse cholesterol transport can lead to lipid accumulation, which induces an inflammatory response, forming subretinal drusenoid deposits. AGEs advanced glycation endproducts, BD basal deposit, BrM Bruch’s membrane, CC choriocapillaris, CEP carboxyethyllysine, Chol cholesterol, ER endoplasmic reticulum, HAP hydroxyapatite, HDL high-density lipoprotein, HFC high-fat cholesterol diet, HSPG heparan sulfate proteoglycan, Lp apoB100 containing lipoprotein, Ly lysosome, Mono/macro monocyte/macrophage, RCT reverse cholesterol transport, ROS reactive oxygen species, SDD subretinal drusenoid deposit; yellow circle surrounded by red, apoB100 containing lipoprotein with surrounding HAP

Fig. 4

Cartoon of inflammatory processes involved in AMD pathobiology. In the subretinal space, oxidized lipids and excess HDLs can elicit an inflammatory response that includes microglial and systemic monocyte recruitment. a Initially, immune responses are heightened, representing parainflammation to maintain cell health. This includes activation of RPE, microglia, and potentially choroidal macrophages, with heightened intracellular cytokine responses (IL-18, IL-33), upregulation of autophagy, and immunometabolic regulation to maintain mitochondrial health. b Conversion from parainflammation to chronic inflammation can induce inflammasome activation by microglia, monocytes and the RPE (including IL-1b production) that contributes to subretinal drusenoid deposit formation. In the RPE, complement and the inflammasome can be activated by a number of triggers. In Bruch’s membrane, the accumulation of lipoproteins and cellular debris elicits an inflammatory response from the RPE, mast cells, and monocytes/macrophages derived from the choroid or systemic circulation to activate both complement and the inflammasome. Inflammatory debris accumulates around lipoproteins/HAP particles during drusen formation in Bruch’s membrane. CEP carboxyethyllysine, CFH complement factor H, HSPG heparan sulfate proteoglycan, Ly lysosome, MDA malondialdehyde, Mit mitochondria, mono/macro monocyte/macrophage, PR photoreceptor, ROS reactive oxygen species, SDD subretinal drusenoid deposit, TLR Toll-like receptor