Alteration of cytokine expression in exudative age-related macular degeneration and its targeting therapy
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Exudative age-related macular degeneration (AMD) is the leading cause of central vision loss in elderly population, and its primary pathological mechanism is the formation of choroidal neovascularization (CNV). Recently, it is found that the balance of angiogenesis and antiangiogenic factors plays an important role in the formation of CNV, and the main factors are vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). The targeting therapy for these cytokines provides a new approach to the treatment of exudative AMD. Anti-VEGF therapy is of great effect on controlling CNV and improving visual acuity in exudative AMD patients. The purpose of this review was to summarize current advance in the study of cytokines associated with the pathogenesis of exudative AMD and its targeting therapy.
Key words:
Aging; Macular degeneration/drug therapy; Choroidal neovascularization; Cytokine; Vascular endothelial growth factor; Pigment epithelium-derived factorKeywords:
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Age-related macular degeneration (AMD) is a common cause of blindness in elderly population. Exploration of effective treatment of AMD has important significance. Pigment epithelial-derived factor (PEDF) is the most powerful endogenous inhibitor of angiogenesis. Increasing evidences, including results of phase I clinical trial, indicated that PEDF could significantly inhibit the development of choroidal neovascularization, which is the characteristic of wet AMD. Therefore, PEDF is one of the most potential therapeutic agents for AMD treatment.
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Age-related macular degeneration (AMD) is one of the most severe vision-threatening diseases. Wet AMD, caused by choroidal neovascularization (CNV), progresses rapidly, while dry AMD, characterized by neural retinal atrophy followed by choroidal vascular atrophy, progresses slowly. In addition to systemic risk factors, such as a high body-mass index (BMI), smoking, hypertension, and atherosclerosis, light-induced local oxidative stress and inflammation promotes AMD. CNV can be induced by multiple pathways. The accumulation of lipofuscin, a product of the undigested outer segments of photoreceptor cells, causes chronic local inflammation. Extracellular lipoprotein deposits, which contain pro-inflammatory components, such as complement, can trigger local inflammation. A single nucleotide polymorphism (SNP) in some genes; i.e., complement factor H (CFH) and excision repair cross-complementing rodent repair deficiency complementation group 6 (ERCC6), which induce local inflammation, is a risk factor for AMD. Two treatments, photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) therapy, have been approved worldwide to cause the regression of CNV. In addition, the suppression of CNV progression combined with retinal neural protection by anti-oxidative reagents such as lutein/zeaxanthin and/or docosahexaenoic acid / eicosapentaenoic acid (DHA/EPA) is a promising prospective therapeutic approach. This is the subject of an ongoing prospective, randomized, double-blind, multicenter clinical trial, the Age-Related Eye Disease Study 2 (AREDS2). In addition, molecular and biological analyses in animal models have provided data supporting this anti-oxidant therapy.
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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.
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Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is the most common cause of severe visual loss in patients over age 60 years in developed countries. While much is unknown about the underlying pathogenesis of CNV, the increased production of vascular endothelial growth factor(VEGF) by retinal pigment epithelium (RPE) is thought to play a central role in the development of this condition. However, recent studies using gene-manipulated mice question the importance of VEGF alone in promoting CNV. Angiogenesis is thought to result from the balance between angiogenesis stimulation and inhibition. A potent antiangiogenic factor recently has been identified in the retina and shown to be secreted by RPE cells. The inhibitor, pigment epithelium-derived factor(PEDF) is considered the key factor associated with avascularity of the cornea, vitreous, and outer retinal layer of the eye. We recently demonstrated that an imbalance between PEDF and VEGF in RPE cells caused by aging and oxidative stress may contribute to the disregulation of endothelial cell proliferation in CNV. In this review, we also discuss the angiogenic role of inflammatory cells in CNV, age-related changes in Bruch's membrane, and the possibility of the development of animal models reflecting CNV in AMD.
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Abstract: Age-related macular degeneration (AMD) is the main cause of visual impairment and blindness in people aged over 65 years in developed countries. Vascular endothelial growth factor (VEGF) is a positive regulator of angiogenesis and its proven role in the pathological neovascularization in wet AMD has provided evidence for the use of anti-VEGF agents as potential therapies. In this study, we review the literature for the possible causes of failure after treatment with anti-VEGF agents and attempt to propose an algorithm of suggestive actions to increase the chances of successful management of such difficult cases. Keywords: antiVEGF, age related macular degeneration, treatment
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MicroRNA (miRNA) refers to a small endogenous non-coding RNA molecule. Its abnormal expression is closely related to the development of age-related macular degeneration (AMD). MiRNA plays an important role in pathogenesis of AMD, including the inflammatory response, oxidative stress injury, amyloid, choroidal neovascularization(CNV) and other lesions development. These findings may provide new possibilities for early diagnosis, treatment and prognosis judgment of AMD. (Int Rev Ophthalmol, 2017, 41: 79-82)
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microRNA; age-related macular degeneration; retinal pigment epithelium; choroidal neovascularization; vascular endothelial growth factor
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Exudative macular degeneration is the major sight-threatening disease in people over 60 years of age in the western world. Molecular remedies based on research in mice have recently been introduced that give some hope of improving the visual outcome in severe cases. Several molecules, including VEGF, MMP, and PEDF, as well as breakdown of the blood-retina barrier comprising RPE and Bruch's membrane, seem to be implicated in the inflammatory processes preceding the development of choroidal neovascularization in age-related macular degeneration. Combination therapies targeting these multifactor processes hold promise for future treatment of CNV in AMD.
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Age-related macular degeneration (AMD) is the major cause of visual loss for people over the age of 65. Vascular endothelial growth factor (VEGF) has been recognized to have a critical role in angiogenesis cascade, including choroidal neovascuarization in wet AMD. Neutralization of VEGF activity is currently the gold standard treatment of wet AMD. In addition to developing new anti-VEGF agents with better efficiency and longer durability, researches on other related potential approaches are undergoing. This article reviews the available as well as the promising therapeutic agents engineered to inhibit the angiogenic pathway for the treatment of wet AMD.
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