Scholarly article on topic 'Age related macular degeneration – challenge for future: Pathogenesis and new perspectives for the treatment'

Age related macular degeneration – challenge for future: Pathogenesis and new perspectives for the treatment Academic research paper on "Clinical medicine"

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{"Age related macular degeneration" / Angiogenesis / "Free oxygen radical" / "Genetic polymorphism"}

Abstract of research paper on Clinical medicine, author of scientific article — K. Michalska-Małecka, A. Kabiesz, M. Nowak, D. Śpiewak

Abstract The authors presents the review of the literature concerning the pathogenesis, classification, risk factors as well as perspectives for the treatment of age-related macular degeneration (AMD). AMD is a progressive illness, which is the most common cause of blindness in developed countries. The degenerative changes associated with both forms (dry and wet AMD) occur in the central part of retina, the macula, but the exact aetiology is still not unclear. The pathogenesis of AMD includes: lipofuscine genesis, drusogenesis, and local inflammatory state, as well as neoangiogenesis. Multiple studies have assessed the role of genetic variants on AMD development and progression, especially with complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes, the two major susceptibility genes for AMD. The disease has been associated with light-induced oxidative damage, accumulation of cholesterol and other lipids, and has been linked to systemic factors such as smoking, hypertension and atherosclerosis. Also female gender, and a high body-mass index (BMI > 30) have been reported as the important demographic and environmental risk factors in AMD. The neovascular form of AMD is characterized by the formation of subretinal choroidal neovascularization (CNV) and is the cause of most cases of blindness in the elders. Currently, the only approved treatment for dry AMD is the use of AREDS formulation. In the near future, it is likely that the treatment of dry AMD will be a combination of different drugs that will target the different pathways involved in the pathogenesis and progression of dry AMD. Exudative AMD is treated through injections of anti-VEGF A drugs as pegaptanib or ranibizumab and bevacizumab, which are considered the standard drugs. Aflibercept, or VEGF Trap-eye, is a novel compound derived from the native VEGF receptor (VEGFR) that binds to all VEGF and VEGF-B isoforms as well as to PlGF. It may be considered an attractive alternative to other anti-VEGF agents.

Academic research paper on topic "Age related macular degeneration – challenge for future: Pathogenesis and new perspectives for the treatment"

■¡HHEIB^H ARTICLE IN PRESS

EUROPEAN ERIATRIC MEDICINE

European Geriatric Medicine xxx (2014) xxx-xxx

ELSEVIER

Research paper

Age related macular degeneration - challenge for future: Pathogenesis and new perspectives for the treatment

K. Michalska-Malecka a,:*, A. Kabiesza, M. Nowakb, D. Spiewaka

a Department of Ophthalmology, University Centre of Ophthalmology and Oncology of Medical University of Silesia, Ceglana Street 35,40-952 Katowice, Poland b Pathophysiology Division, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Traugutta Square 2, 41-800 Zabrze, Poland

ABSTRACT

The authors presents the review of the literature concerning the pathogenesis, classification, risk factors as well as perspectives for the treatment of age-related macular degeneration (AMD). AMD is a progressive illness, which is the most common cause of blindness in developed countries. The degenerative changes associated with both forms (dry and wet AMD) occur in the central part of retina, the macula, but the exact aetiology is still not unclear. The pathogenesis of AMD includes: lipofuscine genesis, drusogenesis, and local inflammatory state, as well as neoangiogenesis. Multiple studies have assessed the role of genetic variants on AMD development and progression, especially with complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes, the two major susceptibility genes for AMD. The disease has been associated with light-induced oxidative damage, accumulation of cholesterol and other lipids, and has been linked to systemic factors such as smoking, hypertension and atherosclerosis. Also female gender, and a high body-mass index (BMI > 30) have been reported as the important demographic and environmental risk factors in AMD. The neovascular form of AMD is characterized by the formation of subretinal choroidal neovascularization (CNV) and is the cause of most cases of blindness in the elders. Currently, the only approved treatment for dry AMD is the use of AREDS formulation. In the near future, it is likely that the treatment of dry AMD will be a combination of different drugs that will target the different pathways involved in the pathogenesis and progression of dry AMD. Exudative AMD is treated through injections of anti-VEGF A drugs as pegaptanib or ranibizumab and bevacizumab, which are considered the standard drugs. Aflibercept, or VEGF Trap-eye, is a novel compound derived from the native VEGF receptor (VEGFR) that binds to all VEGF and VEGF-B isoforms as well as to PlGF. It may be considered an attractive alternative to other anti-VEGF agents.

© 2014 The Authors. Published by Elsevier Masson SAS. All rights reserved.

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ARTICLE INFO

Article history: Received 9 June 2014 Accepted 4 September 2014 Available online xxx

Keywords:

Age related macular degeneration

Angiogenesis

Free oxygen radical

Genetic polymorphism

1. Introduction

Age-related diseases such as age-related macular degeneration (AMD) and cataract will assume increasing importance in the public health of the nation. AMD and cataract are both common causes of visual acuity loss and reduced quality of life in the elderly. Conditions may coexist that limit the final result after cataract surgery [1,2].

AMD is a multi-faceted condition that affects the central retina, which ultimately leads to blindness in millions of people worldwide. The pathophysiology and risk factors for AMD are complex, and the symptoms manifest in multiple related but distinct forms [3]. Untreated AMD can result in blindness, especially in white men or women over the age of sixty with blue irises [4]. With

Corresponding author.

E-mail address: k.michalska.malecka@gmail.com (K. Michalska-Malecka).

progressive deterioration of the macula, AMD patients experience a multitude of visual problems that significantly affect their mental health and quality of life (QoL) [5]. Visual impairment leads to reduced QoL, poorer general health, and increased mortality [6]. The decrease of vision is a serious risk factor for loss of balance, perhaps leading to falls and injury. Many risk factors for falling among elder people have been identified in epidemiological studies, including poor vision [7].

2. Epidemiology

There are around 20 million reported patients with all kinds of AMD, but the total number is probably 100% higher. Data from different research centers are alarming and confirm the high AMD incidence rate [4]. The disease is more common in Caucasian individuals than in pigmented races. In predominantly Caucasian populations, the age-standardized prevalence of AMD in at least one eye is 7760 cases per million. AMD is the most important single

http://dx.doi.org/10.1016/leurger.2014.09.007

1878-7649/® 2014 The Authors. Published by Elsevier Masson SAS. All rights reserved.

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cause of blindness among Caucasian individuals in developed countries. Blindness resulting from AMD rarely occurs before age 70, and most cases occur after age 80. The age-standardized 1-year incidence of legal blindness resulting from AMD is 212 cases per million [8]. In cross-sectional population-based studies La Cour et al. found that about 45% of eyes with AMD have visual acuity reduced to 20/200 or worse [8]. In the US, the estimated prevalence of AMD (neovascular and/or geographic atrophy) is 1.47%, affecting approximately 1.75 million individuals [9]. These numbers are projected to increase by 50% by 2020 and data suggest that more than 3 million people in the United States will be affected by the disease by 2020 [9]. In Japan, which has the oldest and longest living population in the world, 1.64 million people are affected by visual impairment, of whom 61% are older than 65 years. Notably, early AMD is highly prevalent (12.7%) in those 50 years and older in the Japanese population, whereas late AMD is less prevalent (0.87%) [10]. In the newest study, Owen et al. report the prevalence of late AMD standardized to the UK population aged 50 years or older was 2.4%, increasing to 4.8% in those aged 65 years or older, and 12.2% in those aged 80 years or older [11]. In another study, Jonasson et al. in Scandinavian population found a higher prevalence of AMD in the studied group [10]. The prevalence of early AMD was 12.4% for those aged 66-74 years and 36% for those aged >85 years. The authors concluded that persons aged > 85 years have a 10-fold higher prevalence of late AMD than those aged 70-74 years [12]. Over the last few years, life expectancy in Poland has been increasing steadily and the forecasts for the future are optimistic. For men, this rate is predicted to grow from the current 70.4 years to 77.6 years in 2035, while for women, from 78.8 to 83.3 years (compared with respectively 56.0 and 61.6 years in 1950) [13]. In Poland, the estimated prevalence of AMD is 1.2 million people with 10-15% prevalence of exudative form of disease and presently arrives about 100 thousand new patient yearly. About 40-50 thousand are legally blind because of AMD.

3. Classification of AMD

Clinically, there are two types of AMD dry (degenerative) and wet (neovascular) form. The latter form of AMD includes geographic atrophy and more severe disciform (neovascular) variant first described in 1885 by Haab as senile macular degeneration [14].

Dry AMD accounts for about 80% of cases affecting both eyes, but it typically causes only mild loss of vision [15]. Geographic atrophy (GA), the advanced non-neovascular form of AMD, accounts for 35% of all cases of late-stage AMD and 20% of legal blindness attributable to AMD [16]. Dry AMD, which is usually slowly progressing, for unknown reasons can become an aggres-sive-neovascular form of this disease. On account of the complex character of AMD changes, there are many classifications of this disease but the most general seems to be that shown by AREDS [17]. According to this examination there are 4 stages of AMD progression:

• initial (A), with small areas of hyperpigmentation and less than 20 middle-size druses;

• intermediate (B), with one or a few big druses, many middle-size druses or geographical atrophy outside the retinal macula;

• advanced (C and D), with the most progressive changes characteristic of both dry and exudative AMD, which can occur with or without neovascularization.

In clinical practice, the severity of AMD can be categorized based on Snellen visual acuity (VA) testing of the better-seeing eye:

mild (20/20-20/40), moderate (20/50-20/100), severe (20/200 or worse), very severe (20/800 or worse) [18].

4. Pathogenesis and risk factors of AMD

The abnormalities of this disorder range from discrete drusen deposits and pigmentary changes in early AMD to geographic atrophy and/or choroidal neovascularization (CNV) in the advanced forms. Human retina undergoes changes as part of the natural course of aging. AMD is generally associated with pathological changes in the retinal pigment epithelium (RPE) and Bruch's membrane (a collagen-rich extracellular matrix between the RPE and choroidal vasculature) including appearance of ophthalmoscopically visible focal yellow deposition of acellular, polymorphous debris called drusen between the retinal pigment epithelium and Bruch's membrane [19]. Pathogenesis of AMD includes: drusen genesis, lipofuscin genesis, local inflammatory state genesis, as well as angiogenesis [20]. Druses are retinal metabolites' clusters gathered under RPE and the internal layer of the choroid called Bruch's membrane which handicap transport of nutritive components and metabolites. Immune-chemical examinations have shown that druses contain plasma proteins, lipoprotein (apolipoprotein E), cholesterol-rich lipids, polysac-charides, glycoprotein and plasma amyloid P, responsible for complement inactivation and membrane attack complex (MAC) formation. The complement causes intensification of a local inflammatory state and, as a consequence of this, degeneration of photoreceptors and RPE [21]. Drusen are often classified as "hard" or "soft" (also called "large") and while the hard form is common in the aging human eye, soft drusen are more closely associated with risk and progression of AMD [22]. Amorphous druses are heterogeneous. There are a few types of these colloid bodies. The most common are:

• hard, which are hyaline deposits the size of < 65 um;

• soft, the size of > 65 um, of irregular shape, with tendency to form bigger clusters;

• mixed, which appear when hard and soft druses occur simultaneously.

Yellow deposits which appear in RPE basement membrane are called basement lamina druses. Each druse can turn into calcified one. Drusen are also classified as small (<63 mm in diameter with discrete margins), medium (63-124 mm) or large (>125 mm with indistinct edges) [23].

As the human organism ages, numerous metabolites appear in the retina, which can make the process of druse formation and lipofuscin genesis accelerate. Lipofuscin (LF), called cell-aging factor, is a product of incomplete metabolism of external segments of photoreceptors by phagolysosomes. Due to loss of the protein-lipid membrane tightness, liposome lipofuscin gets into cytoplasm and then to extracellular areas, which finally results in forming druses [20]. Molecule LF includes hybrid flurophor A2-E taking an active part in photoreceptors' apoptosis, which suggests that LF is involved in AMD pathogenesis [20]. When present in excessive levels, lipofuscin and A2-E (a toxic vitamin A dimer) damage photoreceptors and choriocapillaris, leading to geographic atrophy. Besides being toxic to the RPE, A2-E has also been shown to activate the complement cascade [24,25].

Long-term epidemiological studies have identified valuable information on the prevalence, incidences, natural history and associated risk factors of AMD [22]. The disease has been associated with light-induced oxidative damage [26], accumulation of cholesterol and other lipids [27], and has been linked to systemic factors such as smoking [28], hypertension and atherosclerosis [29,30]. Cigarette smoking is associated with

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increased oxidative stress, lipid peroxidation, fibrinogen levels, and platelet aggregation. It is also associated with reduced plasma high-density lipoprotein and antioxidant levels [31]. Cigarette smoking can damage choroidal vessels and diminish choroidal blood flow through atherosclerosis. Nicotine promotes angiogen-esis through nicotine-induced up-regulation of VEGF, a proangio-genic factor involved in the pathogenesis of neovascular AMD

[32]. Authors found that cigarette smoking also causes inflammation by activating complement C3 and other inflammatory mediators and reducing serum levels of complement factor H

[33]. Lee et al. found that current cigarette smoking in exudative AMD patients is associated with a poor visual acuity improvement following intravitreal ranibizumab therapy [34]. Cigarette smoking increases the risk of developing AMD, with heavier smokers showing an increasingly greater risk of advanced forms of AMD [35]. Patients diagnosed with early AMD exhibit signs of systemic and retinal vascular alterations that correlated with known risk markers for future cardiovascular morbidity [36]. Significant choroidal vascular alterations, such as changes in choriocapillaris density and volume and choroidal vessel diameter, have been reported both in ageing and AMD [37]. Choroidal ischaemia is well accepted as a causative factor, but its severity and prevalence have not been well documented because of the difficulty in imaging the choroid due to light absorption by the overlying retinal pigment epithelium (RPE) [38]. Coleman et al. based on results of their study found ultrasonographic evidence of choroidal ishcaemia in AMD [38] which is consistent with the results presented by others authors [39]. Other authors concluded that pharmacological agents such as sildenafil, tadalafil, niacin or other agents that increase choroidal perfusion could have a beneficial effect on delaying or interdicting AMD [40]. Cardiovascular risk factors, such as hypertension and hyperlipidemia have been inconsistently associated with AMD risk as well. Elevated serum triglycerides were associated with increasing intermediate AMD in one series while another population found no association with serum lipids

[41]. Apolipoprotein E (apo E) is unique among lipoproteins, because of its special connections with nervous tissue. In the retina, the analogue of the astrocyte, the Muller cells seem to be the site of apo E production. Apo E mobilizes and redistributes lipids, in maintenance and repair of neuronal cell membranes in central nervous system (CNS) injury and neurodegenerative disorders

[42]. Apart from homeostasis of cholesterol and triglicerides, Apo E has also other functions, e.g. immunoregulation, nerve regeneration or activation of lipolic enzymes [43]. Some prior studies have suggested a possible role of apo E polymorphism in development of AMD. It is interesting, that authors have found a reduced risk of AMD in peoples carrying £4 allele, whereas for other neurode-generative disorders and cardiovascular diseases authors have found increased risk for these subjects [44,45]. Apo E may have a significant role in retinal membrane renewal, and cell membrane remodeling in macular area is probably the most important for normal physiology and functions of the retina. Failure of this process may be a risk for development of degenerative disorders of the central retinal area. In other study female gender, and a high body-mass index (BMI > 30) have been reported as the important demographic and environmental risk factors in AMD [46,47]. There are similarities between the drusen formation in AMD and in formation of plaques in Alzheimer's disease (AD). Drusen contain similar protein components to the plaques found in AD. ApoE and amyloid beta (Ab) are found both in AMD drusen as well in AD plaques. The Ab found in drusen is thought to be locally derived from the RPE cells. In the AMD inflammatory process, there is an associated rise in expression of both Ab protein and acute-proteins such as C-reactive protein (CRP) [48]. In the last decade much interest has been focused on the connection between the function of the antioxidative system, concentration of antioxidants and the

presence of age related diseases. The pathogenesis of dry AMD is not completely understood and it is suggested that oxidation and inflammation play important roles in the pathogenesis of the diseases. Apart from adrenal glands, the retinal tissue is one of the tissues with the biggest oxygen needs due to the complexity of its metabolism processes. Processes of cellular respiration occurring in mitochondria are a source of reactive oxygen forms (ROF) which can damage both retinal cones and rods, especially when reductive mechanisms are failing [49]. The human antioxidative system consists of two parts, enzymatic and nonenzymatic part. Enzymatic part of the system includes: catalase, glutathione peroxidase and reductase and superoxide dismutase [50]. Correct activity of these systems is controlled by zinc, selenium, copper and manganese ions. The non-enzymatic part of this system includes vitamins E and C, glutathione as well as carotenoids, and especially lutein and mezoxantine, which are natural components of the macula [51]. Nowak et al. have raised a point that oxidative could be one of the factors involved in the pathogenesis of AMD and suggested the possible protective effect of antioxidants supplementation [52]. Although the rods and cones are replaced every 10 days their outer segments may be at particular risk of the oxidative damage because of high concentration of the poly-unsaturated fatty acids in the photoreceptor outer segment membrane. Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human retina, comprising 60% of the polyunsaturated fatty acids in the retina. It is the most oxidizable fatty acid in the body and is found in the membrane of the outer segment of the photoreceptors. The human macula has a lifelong exposure to light and very high oxygen consumption. The antioxidant index of the body, that includes the measurement of the antioxidative enzymes activity and plasma nonenzymatic components concentration, has been studied in AMD patients by several researchers but the results were contradictory [52-56]. Uruglu et al. found that there is a significant increase in oxidative stress in AMD patients and significant decrease in antioxidant defense measured by the total thiol level and in PON1 activity [54]. Similar results were presented by other authors who found that superoxide dismutase (SOD), gluthatione reductase (GR) and gluthatione peroxidase (GPx) activity are significantly higher and serum vitamin C and total antioxidant capacity significantly decreased in control group than compared with patients with AMD [55-57]. There is more and more evidence that vitamins with antioxidative potential (e.g, vit. A, C and E) are one of the protective factors for vascular endothelium. They decrease inflammation, inhibit platelet aggregation and progression of the atherosclerosis. The results of case-control studies concerning supplementation with antioxidative vitamins are often ambiguous but they generally indicate a decrease in the risk of degenerations and cardiovascular diseases, especially if they are given early [17,58]. In conclusion the finding of the various studies suggests that the patients with both forms of AMD are an altered metabolic state of oxidation-reduction and that it is convenient to give therapeutic interventions with antioxidants supplementation.

Inflammation has been hypothesized to have a role in the pathogenesis of age-related macular degeneration (AMD) [59]. Medzhitov first introduced the idea of para-inflammation as a tissue adaptive response to noxious stress or malfunction that has characteristics intermediate between basal and inflammatory states [60]. Para-inflammation has characteristics that are intermediate between basal and inflammatory states. In the aging retina, oxidized lipoproteins and free radicals are major causes of tissue stress and serve as local triggers for retinal para-inflammation. Para-inflammatory responses in the retina may be reflected in microglial activation and subretinal migration, and breakdown of blood-retinal barrier. Drusen have been shown to contain proteins associated with immune-mediated processes and inflammation,

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and inflammatory cells have been found on the outer surface of Bruch's membrane in AMD eyes [61]. It has been hypothesized that infectious agent activation of an aberrantly regulated alternative complement pathway might contribute to the development of AMD [62]. Earlier data from a sample of a cohort study showed an association of Chlamydia pneumoniae antibody titers with the 7-year progression of AMD [53]. Data from two small case control studies also showed an association with Chlamydia pneumoniae, but not other pathogens with AMD [63,64]. In a previous study authors reported racial/ethnic differences in the frequency of early AMD with decreasing overall frequencies found in whites (5.4%), Chinese (4.6%), Hispanics (4.2%), and blacks (2.4%) in the Multi Ethnic Study of Atherosclerosis [65]. The reasons for these racial/ ethnic differences, especially between whites and blacks, were not explained by known risk factors such as cigarette smoking, history of alcohol drinking, BMI, hypertension, diabetes status, and markers of subclinical cardiovascular disease [65]. Van de Ven et al. showed that a history of inflammatory diseases or use of anti-inflammatory agents, or biomarkers of inflammation and related processes also did not explain racial/ethnic differences in prevalence of early AMD among the different racial/ethnic groups [66]. Authors found that whites, blacks, and Hispanics who were all homozygous for the complement factor H (CFH) Y402H CC variant genotype had the highest frequencies of early AMD compared with those with the CFH Y402H TT wild genotype. The CFH Y402H CC variant genotype distributions varied among the racial/ethnic groups and did explain some of the difference in early AMD prevalence for Chinese and for Hispanics but did not explain the difference in AMD prevalence between whites and blacks [66]. Genetic studies have implicated roles for the immune system, particularly abnormalities in the complement system in pathogenesis and severity of AMD. Although patients with AMD do not have signs of overt ocular inflammation, histologic studies have shown the presence of macrophages, lymphocytes, and mast cells, as well as fibroblasts, associated with both atrophic lesions and with neovascularization of the retina [67]. Over the past decade, studies has found that inflammation play a large role in the pathogenesis of age-related macular degeneration (AMD). In fact, the main genetic changes (polymorphism) associated with AMD were found to be genes that regulate inflammation, most notably CFH [68]. Complement factor H is a circulating protein that inhibits directly or indirectly the three complement activation pathways. In patients with early and late AMD, many CFH polymorphisms have been described [69]. With abnormal CFH, complement system downregulation is defective and excess inflammation may result. Additionally, histological analysis of drusen revealed the presence of complement factors and the terminal membrane attack complex [70]. It is still unknown whether those complement factors are systemically or locally produced in the retina [71]. Chronic subclinical local inflammation of the retina in AMD patients may trigger and/or sustain the damaging process [59,60]. Despriet et al. found that markers of inflammation, such as serum C-reactive protein (CRP) are related to AMD only in carriers of CFH Y402H variants [72]. Multiple studies have assessed the role of genetic variants on AMD development and progression, especially with CFH and age-related maculopathy susceptibility 2 (ARMS2) genes, the two major susceptibility genes for AMD. CFH Y402H heterozygotes allele conferred 4.6-fold increased risk for AMD and the homozygotes a 7.4-fold increased risk, as compared with the homozygous non-risk genotype [73]. Individuals heterozygotous for ARMS2 A69S allele conferred 2.7-fold increased risk of AMD compared with wild-type homozygous allele, whereas a 8.2-fold increased risk is associated with the homozygous risk allele. An additive effect of CFH Y402H and LOC387715 A69S is seen with 50-fold increase in the risk of AMD in subjects homozygous for both risk alleles

[74]. CFH, ARMS2 these two allelic variants contribute to late AMD in more than 80% of cases [74,75]. Other genes that harbor established risk variants for AMD include the complement factor B (CFB), complement component 2 (C2), complement component 3 (C3), complement factor I (CFI), and the apolipoprotein E (APOE) genes [76]. The last stage of the complement inactivation (classical and lectyne) is the occurrence of the membrane attack complex (MAC) [77]. Convertase C3 is crucial here, and nine mutations of the single nucleotide, including R102G by its influence on cellular disintegration, are closely connected with exudative AMD [77].

The neovascular form of age-related macular degeneration (AMD), also known as wet AMD, is characterized by the formation of subretinal choroidal neovascularization (CNV) and is the cause of most cases of blindness in the elders. Wet AMD is the major cause of severe vision loss in developed nations and is estimated to affect > 2.5 million people worldwide [78,79]. The patients affected by exudative AMD often experience rapid loss of fine resolution central vision over several months, and early visual stabilization is a key issue in preserving visual acuity [80]. Angio-genesis is the development of new blood vessels from pre-existing vessels and whilst being a crucial process in normal physiology, it is an important pathogenic process in both benign and malignant disease [81]. A lot of markers, both stimulating and inhibiting can influence on this process. Activators of angiogenesis include: VEGF, nitric oxide (NO), integrins: a5b1, avb3 and avb5, transforming growth factor beta 1 (TGFbl) and its receptors, growth factors: acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), insulin-like growth factor I (IGF-I), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), hypoxia-inducible factor 1 alpha (HlF-1a), IL-8, lL-1, prostaglandin (PGE 1, PGE 2, PGF), erythropoietin, histamine, bradykinin, tumour necrosis factor alpha (TNFa) [82,83]. Abnormal angiogenesis is a hallmark of diseases such as cancer, chronic inflammation and also the neovascular form of AMD [84,85]. Choroidal neovascularization (CNV) represents the growth of new blood vessels from the choroid into the subretinal pigment epithelium. Several proangiogenic factors are consistently upregulated during CNV formation, particularly two members of the vascular endothelial growth factor (VEGF) family, VEGF-A and placental growth factor (PlGF) [84,86]. These factors activate quiescent endothelial cells and promote cell proliferation, migration and vascular permeability [84].

5. Treatment of AMD

While a treatment for geographical atrophy (GA) remains to be established, treatments for neovascular AMD using photodynamic therapy and antivascular endothelial growth factors exist. Currently, the only approved treatment for dry AMD is the use of AREDS formulation [17,58,87]. In the near future, it is likely that the treatment of dry AMD will be a combination of different drugs that will target the different pathways involved in the pathogen-esis and progression of dry AMD [88]. Firstly pharmacological targeting of components involved in dry AMD pathogenesis is prevention of photoreceptors and RPE cells loss. Ciliary neuro-trophic factor (CNTF) is a potent neurotrophic factor that slows down loss of photoreceptors in various animal models of retinal degeneration [89], and there are evidences of its efficacy in human retinitis pigmentosa [90]. Alpha-2 adrenergic receptor is present in the mammalian retina and brimonidine tartrate (Allergan lnc., USA, an alpha-2 adrenergic receptor agonist has been shown to protect retinal ganglion cells, bipolar cells, and photoreceptors in numerous models of experimental nerve injury, including retina ischemia, ocular hypertension, retinal phototoxicity, and partial optic nerve crush [91]. Other authors in an animal model found

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that a selective serotonin 1A agonist (Tandospirone, Alcon Laboratories Inc., USA) protects photoreceptors and RPE cells from photo-oxidative stress by decreasing microglia activation/recruitment and complement deposition in the outer retinax [92]. The analysis of the drusen in patients with Alzheimer disease treated with glatiramer acetate (an immunomodulatory drug currently used to treat multiple sclerosis) showed that the drug reduces drusen area. Specifically in patients with dry AMD, glatiramer acetate shrank or eliminate more drusen than did sham treatment [93].

Secondly pharmacological targeting of components involved in dry AMD pathogenesis is suppression of inflammation. It is likely that if inflammation will be reduced, development or progression of AMD will also be reduced. Inflammatory elements are present in drusen, such as components of the complement system, acute-phase proteins, proteins that modulate the immune response, lipofuscin, and dendritic cells [71]. In an animal model study authors found that fluocinolone acetonide is a potent corticoster-oid that presented a neuroprotective effect by dampening retinal neuroinflammation [94,95]. Several therapeutic agents involved in the complement cascade are under investigation [88]. POT-4 (Potentia Pharmaceuticals, USA) is a synthetic peptide that reversibly binds complement factor C3 and inhibits activation of the complement cascade (ClinicalTrials.gov number, NCT00473928). Eculizumab (Alexion Pharmaceuticals, USA) is a humanized IgG antibody that selectively inhibits the cleavage of C5 factor into C5a and 5b (ClinicalTrials.gov number, NCT00935883). ARC1905 (Ophthotech Corp., USA) is an aptamer that is a potent and selective inhibitor of factor C5 of the complement cascade (ClinicalTrials.gov number, NCT 00950638). FCFD4514S (Genentech Inc., USA) is a human monoclonal antibody that inhibits complement factor D, a protein involved in the alternative complement pathway (ClinicalTrials.gov numbers, NCT 00973011) [88]. Treatment of dry AMD still remains a challenge. Currently, the only approved treatment for dry AMD is the use of Age-Related Eye Disease Study (AREDS)-based vitamin supplements, which does not halt the vision loss but lowers the risk of developing advanced stages of AMD (either geographic atrophy or neovascular AMD) and reduces visual loss in people at risk for the disease [17,87]. The AREDS established that antioxidant vitamin and mineral supplementation (AREDS formulation) consisting of b-carotene (15 mg), vitamins C (500 mg) and E (400 IU), and zinc (as zinc oxide 80 mg), along with copper (as cupric oxide 2 mg) slowed progression of AMD in individuals at high risk of developing advanced AMD [87]. Recent analyses demonstrate that the beneficial effects are restricted mostly to preventing the progression to neovascular AMD [69].

The arsenal of VEGF blockers has evolved over time, with newer generations offering potentially improved anti-angiogenic activity by increasing their affinity for VEGF-A, and/or the number of VEGF-isoforms and family members that they inhibit. Pegaptanib (Macugen™, Eyetech, Inc.) is an aptamer that selectively binds to and neutralizes VEGF-A165, but not VEGF-A121, and was the first anti-VEGF therapy approved for the treatment of wet AMD [96]. The development of new agents for wet AMD has focused on both improving efficacy and extending the duration of action in comparison with the commonly used anti-VEGF drugs ranibizu-mab and bevacizumab, which are considered the standard drugs. Ranibizumab is a monoclonal humanized antibody fragment and bevacizumab is a whole monoclonal antibody, and both show a high binding affinity for all isoforms of VEGF. These agents appear to have similar efficacy profiles and mechanisms of action, i.e., they block the extracellular availability of VEGF which can arrest choroidal angiogenesis and reduce vascular permeability for a limited period of time [97,98]. Aflibercept, or VEGF Trap-eye, is a novel compound derived from the native VEGF receptor (VEGFR)

that binds to all VEGF and VEGF-B isoforms as well as to PlGF [99]. It may be considered an attractive alternative to other anti-VEGF agents because it appears to offer visual outcomes similar to ranibizumab and bevacizumab with a longer duration of action. For the first time, an anti-VEGF drug can be given at 2-month intervals with results comparable to ranibizumab given every 4 weeks [100]. The data demonstrate that VEGF trap binds human VEGF-A with higher affinity and a significantly faster association rate, thus neutralizing VEGF-A with greater potency than ranibizumab or bevacizumab [99].

Projections over the next decade suggest that the number of prevalent cases of late AMD will increase steadily by a third by 2020 due to population ageing. These evidence-based estimates can be used to help plan social and healthcare provision for the present and the future.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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