scholarly journals Associations between the Complement System and Choroidal Neovascularization in Wet Age-Related Macular Degeneration

2020 ◽  
Vol 21 (24) ◽  
pp. 9752
Author(s):  
Emilie Grarup Jensen ◽  
Thomas Stax Jakobsen ◽  
Steffen Thiel ◽  
Anne Louise Askou ◽  
Thomas J. Corydon
Keyword(s):  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Complement System ◽  
Complex Disease ◽  
Vision Loss ◽  
Alternative Pathway ◽  
Age Related Macular Degeneration ◽  
Western World ◽  
Age Related ◽  
The Complement System

Age-related macular degeneration (AMD) is the leading cause of blindness affecting the elderly in the Western world. The most severe form of AMD, wet AMD (wAMD), is characterized by choroidal neovascularization (CNV) and acute vision loss. The current treatment for these patients comprises monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) antibodies, but this treatment is expensive, uncomfortable for the patient, and only effective in some individuals. AMD is a complex disease that has strong associations with the complement system. All three initiating complement pathways may be relevant in CNV formation, but most evidence indicates a major role for the alternative pathway (AP) and for the terminal complement complex, as well as certain complement peptides generated upon complement activation. Since the complement system is associated with AMD and CNV, a complement inhibitor may be a therapeutic option for patients with wAMD. The aim of this review is to (i) reflect on the possible complement targets in the context of wAMD pathology, (ii) investigate the results of prior clinical trials with complement inhibitors for wAMD patients, and (iii) outline important considerations when developing a future strategy for the treatment of wAMD.

scholarly journals Pathogenesis in Wet-Form (Neovascular) Age-Related Macular Degeneration

2017 ◽  
pp. 173-177
Keyword(s):  
Oxidative Damage ◽  
Macular Degeneration ◽  
Chronic Inflammation ◽  
Choroidal Neovascularization ◽  
Complement System ◽  
Molecular Targets ◽  
Age Related Macular Degeneration ◽  
Neovascular Amd ◽  
Age Related ◽  
The Complement System

The understanding of the pathogenesis of the development of choroidal neovascularization (CNV) in age-related macular degeneration (AMD) continues to evolve. Epidemiological, histopathological, and biochemical evidence indicates that neovascular AMD is associated with oxidative damage, lipofuscin accumulation, chronic inflammation, and mutation in the complement system. Molecular targets have been identified that serve as the basis for developing new, better treatments for neovascular AMD.

scholarly journals Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Shuqi Qin ◽  
Ning Dong ◽  
Ming Yang ◽  
Jialin Wang ◽  
Xue Feng ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Macular Degeneration ◽  
Complement System ◽  
Vision Loss ◽  
Age Related Macular Degeneration ◽  
Phase Iii ◽  
Complement Inhibitors ◽  
Age Related ◽  
Dry Amd ◽  
The Complement System

Age-related macular degeneration (AMD) is a multifactorial disease, which can culminate in irreversible vision loss and blindness in elderly. Nowadays, there is a big gap between dry AMD and wet AMD on treatment. Accounting for nearly 90% of AMD, dry AMD still lacks effective treatment. Numerous genetic and molecular researches have confirmed the significant role of the complement system in the pathogenesis of AMD, leading to a deeper exploration of complement inhibitors in the treatment of AMD. To date, at least 14 different complement inhibitors have been or are being explored in AMD in almost 40 clinical trials. While most complement inhibitors fail to treat AMD successfully, two of them are effective in inhibiting the rate of GA progression in phase II clinical trials, and both of them successfully entered phase III trials. Furthermore, recently emerging complement gene therapy and combination therapy also offer new opportunities to treat AMD in the future. In this review, we aim to introduce genetic and molecular associations between the complement system and AMD, provide the updated progress in complement inhibitors in AMD on clinical trials, and discuss the challenges and prospects of complement therapeutic strategies in AMD.

scholarly journals The complement system in age-related macular degeneration

2021 ◽  
Author(s):  
Angela Armento ◽  
Marius Ueffing ◽  
Simon J. Clark
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Complement System ◽  
Complement Activation ◽  
Molecular Mechanisms ◽  
Alternative Pathway ◽  
Disease Onset ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Complement System

AbstractAge-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.

Changes in complement activation products after anti-VEGF injection for choroidal neovascularization in age-related macular degeneration and pachychoroid disease

2020 ◽  
Author(s):  
Keiichiro Tanaka ◽  
Yasuharu Oguchi ◽  
Tomoko Oomori ◽  
Yumi Ishida ◽  
Hiroaki Shintake ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Complement System ◽  
Complement Activation ◽  
Age Related Macular Degeneration ◽  
Anti Vegf ◽  
Age Related ◽  
Activation Products ◽  
The Complement System ◽  
Vegf Level

Abstract We evaluated changes in the complement system resulting from anti-vascular endothelial growth factor (VEGF) in eyes with age-related choroidal neovascularization (CNV) including neovascular age-related macular degeneration, pachychoroid neovasculopathy, and polypoidal choroidal neovasculopathy. We measured the concentrations of the complement activation products (C3a, C4a), VEGF, and monocyte chemotactic protein-1 in the aqueous humor during intravitreal anti-VEGF injections for CNV. The VEGF level decreased significantly (P < 0.001), while the C3a and C4a levels increased significantly (P < 0.001 for both comparisons) 1 month after two monthly anti-VEGF injections. The VEGF level was correlated with the C3a (R = 0.328, P = 0.007) and C4a (R = -0.237, P = 0.055) levels at baseline, but the correlation between the VEGF and C3a levels (R = -0.148, P = 0.242) changed significantly (P = 0.028 by analysis of covariance) after anti-VEGF treatment. The C3a increase after anti-VEGF therapy did not change the visual outcomes in eyes with CNV for 1 year. Dysregulation of the complement system can be induced by excessive reduction of intraocular VEGF after anti-VEGF therapy.

scholarly journals Changes in complement activation products after anti-VEGF injection for choroidal neovascularization in age-related macular degeneration and pachychoroid disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Keiichiro Tanaka ◽  
Yasuharu Oguchi ◽  
Tomoko Omori ◽  
Yumi Ishida ◽  
Hiroaki Shintake ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Complement System ◽  
Complement Activation ◽  
Age Related Macular Degeneration ◽  
Anti Vegf ◽  
Age Related ◽  
Activation Products ◽  
The Complement System ◽  
Vegf Level

AbstractWe evaluated changes in the complement system resulting from anti-vascular endothelial growth factor (VEGF) in eyes with age-related choroidal neovascularization (CNV) including neovascular age-related macular degeneration, pachychoroid neovasculopathy, and polypoidal choroidal neovasculopathy. We measured the concentrations of the complement activation products (C3a, C4a), VEGF, and monocyte chemotactic protein-1 in the aqueous humor during intravitreal anti-VEGF injections for CNV. The VEGF level decreased significantly (P < 0.001), while the C3a and C4a levels increased significantly (P < 0.001 for both comparisons) 1 month after two monthly anti-VEGF injections. The VEGF level was correlated with the C3a (R = 0.328, P = 0.007) and C4a (R = − 0.237, P = 0.055) levels at baseline, but the correlation between the VEGF and C3a levels (R = − 0.148, P = 0.242) changed significantly (P = 0.028 by analysis of covariance) after anti-VEGF treatment. The C3a increase after anti-VEGF therapy did not change the visual outcomes in eyes with CNV for 1 year. Dysregulation of the complement system can be induced after anti-VEGF therapy.

scholarly journals Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 635
Author(s):  
Monica L. Hu ◽  
Joel Quinn ◽  
Kanmin Xue
Keyword(s):  
Risk Factor ◽  
Apolipoprotein E ◽  
Macular Degeneration ◽  
Amyloid Beta ◽  
Complement System ◽  
Genetic Risk ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Retinal Inflammation ◽  
The Complement System

Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer's disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.

Age-related macular degeneration and the complement system

Immunobiology ◽  
2012 ◽  
Vol 217 (2) ◽  
pp. 127-146 ◽  
Author(s):  
S. Khandhadia ◽  
V. Cipriani ◽  
J.R.W. Yates ◽  
A.J. Lotery
Keyword(s):  
Macular Degeneration ◽  
Complement System ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Complement System

scholarly journals Potential Sources and Roles of Adaptive Immunity in Age-Related Macular Degeneration: Shall We Rename AMD into Autoimmune Macular Disease?

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Serge Camelo
Keyword(s):  
T Cells ◽  
Macular Degeneration ◽  
Retinal Degeneration ◽  
Adaptive Immunity ◽  
Choroidal Neovascularization ◽  
Vision Loss ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Pathologic Features

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly throughout the industrialized world. Its most prominent pathologic features are lesions involving the retinal pigment epithelium (RPE) the Bruch’s membrane, the degeneration of photoreceptors, and, in the most aggressive cases, choroidal neovascularization. Genetic associations between the risk of developing AMD and polymorphism within components of the complement system, as well as chemokine receptors expressed on microglial cells and macrophages, have linked retinal degeneration and choroidal neovascularization to innate immunity (inflammation). In addition to inflammation, players of the adaptive immunity including cytokines, chemokines, antibodies, and T cells have been detected in animal models of AMD and in patients suffering from this pathology. These observations suggest that adaptive immunity might play a role in different processes associated with AMD such as RPE atrophy, neovascularization, and retinal degeneration. To this date however, the exact roles (if any) of autoantibodies and T cells in AMD remain unknown. In this review we discuss the potential effects of adaptive immune responses in AMD pathogenesis.

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