Recent developments in the treatment of age-related macular degeneration

Holz, Frank G.; Schmitz-Valckenberg, Steffen; Fleckenstein, Monika

doi:10.1172/jci71029

Cited by 184 publications

(178 citation statements)

References 82 publications

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“…To date, approaches to target the complement pathway in macular degenerations have focused on complement proteins, with varying success (37). Our studies move beyond this narrow focus by providing insight into how the RPE deals with complement at a cellular level and by identifying drugs that can strengthen innate mechanisms essential for preserving RPE health.…”

Section: Discussionmentioning

confidence: 99%

Protective responses to sublytic complement in the retinal pigment epithelium

Tan

Toops

Lakkaraju

2016

Proc. Natl. Acad. Sci. U.S.A.

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The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration. Using polarized primary RPE and the pigmented Abca4 −/− Stargardt disease mouse model, we provide evidence for two protective responses occurring within minutes of complement attack, which are essential for maintaining mitochondrial health in the RPE. First, accelerated recycling of the membrane-bound complement regulator CD59 to the RPE cell surface inhibits MAC formation. Second, fusion of lysosomes with the RPE plasma membrane immediately after complement attack limits sustained elevations in intracellular calcium and prevents mitochondrial injury. Cholesterol accumulation in the RPE, induced by vitamin A dimers or oxidized LDL, inhibits these defense mechanisms by activating acid sphingomyelinase (ASMase), which increases tubulin acetylation and derails organelle traffic. Defective CD59 recycling and lysosome exocytosis after complement attack lead to mitochondrial fragmentation and oxidative stress in the RPE. Drugs that stimulate cholesterol efflux or inhibit ASMase restore both these critical safeguards in the RPE and avert complement-induced mitochondrial injury in vitro and in Abca4 −/− mice, indicating that they could be effective therapeutic approaches for macular degenerations.he complement system is an important regulator of immunity and inflammation. Complement activation by the classical, alternative, or lectin pathways results in the assembly of C5b-9 membrane attack complexes (MACs), which form membrane pores and cause target cell lysis. Within the eye, a low level of constant complement activity is necessary for immune surveillance, and several membrane-bound and soluble regulators prevent excessive complement activation (1). An imbalance between complement activation and inhibition in the retina is implicated in the pathogenesis of age-related macular degeneration (AMD), which causes central vision loss in more than 30 million people globally (reviewed in refs. 2-4).Evidence suggests that the retinal pigment epithelium (RPE), which helps maintain ocular immune privilege, is the first line of defense against unregulated complement activation in the retina (5). The complement cascade is activated by insults that disturb RPE homeostasis, including defective clearance of phagocytosed photoreceptor outer segments (6) and abnormal accumulation of vitamin A dimers (7-9) or oxidized lipids (10) in the RPE. Studies also show that exposure to sublytic levels of MAC alters RPE barrier integrity, causes...

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Section: Discussionmentioning

confidence: 99%

Protective responses to sublytic complement in the retinal pigment epithelium

Tan

Toops

Lakkaraju

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The RPE is considered as one of the critical sites for oxidative injury to cause retinal degeneration in AMD (Cai et al 2000;Hageman et al 2001;Liang and Godley 2003). Geographic atrophy is the term used to describe the degeneration of the RPE and overlying photoreceptors in the advanced form of dry AMD (Holz et al 2014). Anti-oxidant enzymes including manganese superoxide dismutase (MnSOD, coded for by the mouse Sod2 gene) and catalase play an important role in regulating oxidative stress by reducing the levels of superoxide and hydrogen peroxide, respectively.…”

Section: Introductionmentioning

confidence: 99%

Conditional Induction of Oxidative Stress in RPE: A Mouse Model of Progressive Retinal Degeneration

Biswal

Ildefonso

Mao

et al. 2015

Retinal Degenerative Diseases

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An appropriate animal model is essential to screening drugs or designing a treatment strategy for geographic atrophy. Since oxidative stress contributes to the pathological changes of the retinal pigment epithelium (RPE), we are reporting a new mouse AMD model of retinal degeneration by inducing mitochondrial oxidative stress in RPE. Sod2 the gene for manganese superoxide dismutase (MnSOD) was deleted in RPE layer using conditional knockout strategy. Fundus microscopy, SD-OCT and electroretinography were used to monitor retinal structure and function in living animals and microscopy was used to assess pathology post mortem. Tissue specific deletion of Sod2 caused elevated signs of oxidative stress, RPE dysfunction and showed some key features of AMD. Due to induction of oxidative stress, the conditional knockout mice show progressive reduction in ERG responses and thinning of outer nuclear layer (ONL) compared to non-induced littermates.

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“…Nicotinamide reduced C3 mRNA by approximately 90%, and secreted protein levels 6-7-fold. This is significant since complement inhibitors are being designed and tested in clinical trials for AMD (26). Subretinal injections of Aβ 42 in mice induce anatomical defects in RPE and pronounced photoreceptor atrophy (27).…”

Section: Nicotinamide Suppresses Signaling Cascades In Rpe That Mightmentioning

confidence: 99%

Nicotinamide: a novel treatment for age-related macular degeneration?

Westenskow

2017

Stem Cell Investig.

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Saini et al. recently reported in Cell StemCell that nicotinamide can suppress the expression of a broad set of genes in induced pluripotent stem cell-derived retinal pigment epithelium (iPS-RPE) cells that may contribute to age-related macular degeneration (AMD) (1). There are ample reasons to be excited about their findings, and many opportunities for future work. In this commentary, I will begin by providing background about the etiology of AMD before outlining some of the challenges of studying AMD using iPS-RPE. With that context in place, I will describe which elements of the Saini et al. study I find most exciting, and discuss potential future directions. The outer retina-a finely tuned machineThe outer half of the retina consists of hard working cells and structures that convert light into neural signals through phototransduction. Rod and cone photoreceptors initiate phototransduction when activated by light, but cannot complete the process without help from the multifunctional retinal pigment epithelium (RPE) or without fuel. Energy substrates for the RPE and photoreceptors are provided by a highly dense and fenestrated extraretinal vascular plexus, the choriocapillaris, which surrounds the outer retina ( Figure 1A).The choriocapillaris, RPE cells, and photoreceptors are all uniquely remarkable. According to many accounts, the blood flow rate and the vascular permeability of the choriocapillaris is higher than anywhere in the body (2).Oxygen and nutrients from the choriocapillaris are filtered and redistributed in the subretinal space through a pentalaminar matrix (Bruch's membrane) and by RPE cells. RPE also generate and secrete key vasculotrophic factors for choriocapillaris maintenance, deliver glucose to photoreceptors, recycle spent photopigments, absorb stray light, and phagocytose light damaged photoreceptor membranes to prevent oxidative stress (3). Photoreceptors can be activated by a single photon, and can respond appropriately to the wavelength and intensity of a light source. However, they are also extraordinarily metabolically demanding and inherently fragile (4). Maintaining the integrity and homeostasis of photoreceptors, RPE, and the choriocapillaris is imperative, and defects result in profound vision loss. Even finely tuned machines break down over timeThe prevalence of age-related vision loss should not be surprising considering the intense burdens placed on the choriocapillaris and RPE to support the remarkable metabolic demands of photoreceptors. In fact, AMD is a commonly occurring and leading cause of vision loss in industrialized countries. The global prevalence of AMD is steadily increasing and expected to reach epidemic proportions by the year 2040 when some experts estimate that 288 million people could be affected (5). To emphasize Editorial

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Recent developments in the treatment of age-related macular degeneration

Cited by 184 publications

References 82 publications

Protective responses to sublytic complement in the retinal pigment epithelium

Protective responses to sublytic complement in the retinal pigment epithelium

Conditional Induction of Oxidative Stress in RPE: A Mouse Model of Progressive Retinal Degeneration

Nicotinamide: a novel treatment for age-related macular degeneration?

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