scholarly journals A Review of Completed and Ongoing Complement Inhibitor Trials for Geographic Atrophy Secondary to Age-Related Macular Degeneration

2021 ◽  
Vol 10 (12) ◽  
pp. 2580
Author(s):  
Omar A. Halawa ◽  
Jonathan B. Lin ◽  
Joan W. Miller ◽  
Demetrios G. Vavvas
Keyword(s):  
Macular Degeneration ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Western World ◽  
Complement Factor ◽  
Complement Protein ◽  
Pivotal Phase ◽  
Complement Inhibition ◽  
Exudative Amd ◽  
Age Related

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among older adults in the Western world. While therapies exist for patients with exudative AMD, there are currently no approved therapies for non-exudative AMD and its advanced form of geographic atrophy (GA). The discovery of genetic variants in complement protein loci with increased susceptibility to AMD has led to the investigation of the role of complement inhibition in AMD with a focus on GA. Here, we review completed and ongoing clinical trials evaluating the safety and efficacy of these studies. Overall, complement inhibition in GA has yielded mixed results. The inhibition of complement factor D has failed pivotal phase 3 trials. Studies of C3 and C5 inhibition meeting their primary endpoint are limited by high rates of discontinuation and withdrawal in the treatment arm and higher risks of conversion to exudative AMD. Studies evaluating other complement members (CFB, CFH, CFI and inhibitors of membrane attack complex—CD59) are ongoing and could offer other viable strategies.

Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology

2010 ◽  
Vol 38 (5) ◽  
pp. 1342-1348 ◽  
Author(s):  
Simon J. Clark ◽  
Paul N. Bishop ◽  
Anthony J. Day
Keyword(s):  
Macular Degeneration ◽  
Dermatan Sulfate ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor H ◽  
Western World ◽  
Complement Factor ◽  
Coat Proteins ◽  
Age Related ◽  
Increased Risk

AMD (age-related macular degeneration) is the major cause of blindness in the western world, associated with the formation of extracellular deposits called drusen in the macula, i.e. the central region of the retina. These drusen contain cellular debris and proteins, including components of the complement system such as the regulator CFH (complement factor H); dysregulation of complement is thought to play a major role in the development of AMD. CFH acts through its capacity to recognize polyanionic structures [e.g. sulfated GAGs (glycosaminoglycans)] found on host tissues, and thereby inactivates any C3b that becomes deposited. Importantly, a common polymorphism in CFH (Y402H) has been strongly associated with an increased risk of AMD. This polymorphism, which causes a tyrosine to histidine coding change, has been shown to alter the binding of CFH to sulfated GAGs, as well as to other ligands including C-reactive protein, necrotic cells and bacterial coat proteins. Of these, the change in the GAG-recognition properties of CFH is likely to be of most significance to AMD. Recent research has revealed that the disease-associated 402H allotype interacts less well (compared with 402Y) with binding sites within the macula (e.g. Bruch's membrane), where the GAGs heparan sulfate and dermatan sulfate play a major role in mediating the interaction with CFH. Reduced binding of the 402H allotype could result in impaired regulation of complement leading to chronic local inflammation that may contribute to the accumulation of drusen and thus the initiation, development and progression of AMD.

scholarly journals Systemic complement levels in patients with age-related macular degeneration carrying rare or low frequency variants in the CFH gene

2021 ◽  
Author(s):  
Sarah de Jong ◽  
Anita de Breuk ◽  
Elena B Volokhina ◽  
Bjorn Bakker ◽  
Alejandro Garanto ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Rare Variants ◽  
Low Frequency ◽  
Missense Variant ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Western World ◽  
Complement Factor ◽  
Age Related

Abstract Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. Genetic variants in the complement factor H (CFH) gene are associated with AMD, but the functional consequences of many of these variants are currently unknown. In this study we aimed to determine the effect of 64 rare and low frequency variants in the CFH gene on systemic levels of factor H (FH) and complement activation marker C3bBbP using plasma samples of 252 carriers and 159 non-carriers. Individuals carrying a heterozygous nonsense, frameshift or missense variant in CFH presented with significantly decreased FH levels, and significantly increased C3bBbP levels in plasma compared to non-carrier controls. FH and C3bBbP plasma levels were relatively stable over time in samples collected during follow-up visits. Decreased FH and increased C3bBbP concentrations were observed in carriers compared to non-carriers of CFH variants among different AMD stages, with the exception of C3bBbP levels in advanced AMD stages, which were equally high in carriers and non-carriers. In AMD families, FH levels were decreased in carriers compared to non-carriers, but C3bBbP levels did not differ. Rare variants in the CFH gene can lead to reduced FH levels or reduced FH function as measured by increased C3bBbP levels. The effects of individual variants in the CFH gene reported in this study will improve the interpretation of rare and low frequency variants observed in AMD patients in clinical practice.

scholarly journals Complement Inhibition for Geographic Atrophy: A Tempting Target with Mixed Results

2021 ◽  
Vol 10 (13) ◽  
pp. 2890
Author(s):  
Jonathan B. Lin ◽  
Omar A. Halawa ◽  
Joan W. Miller ◽  
Demetrios G. Vavvas
Keyword(s):  
Randomized Clinical Trials ◽  
Strong Association ◽  
Historical Context ◽  
Geographic Atrophy ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Complement Inhibition ◽  
Advantages And Disadvantages ◽  
Age Related

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. One of the strongest genetic risk factors for AMD is a complement factor H (CFH) gene polymorphism characterized by a tyrosine-histidine change at amino acid position 402 (Y402H). The magnitude of this association between the Y402H variant and AMD is among the strongest that has been identified for any complex, multifactorial human disease. This strong association has motivated researchers to investigate a potential link between various elements of the complement pathway and AMD pathogenesis. Given the possible contribution of complement dysregulation to AMD, complement inhibition has emerged as a therapeutic strategy for slowing geographic atrophy (GA). Randomized clinical trials thus far have yielded mixed results. In this article, we provide the historical context for complement inhibition as a strategy for treating GA, discuss potential advantages and disadvantages of complement inhibition, and highlight the questions that must be addressed before complement inhibition can take center stage as a therapy for AMD.

Complement factor B gene polymorphisms and risk of age-related macular degeneration: A meta-analysis

2019 ◽  
Vol 30 (4) ◽  
pp. 743-755
Author(s):  
Yun Su ◽  
Zizhong Hu ◽  
Ting Pan ◽  
Lu Chen ◽  
Ping Xie ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Subgroup Analysis ◽  
Meta Analysis ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Factor B ◽  
Complement Factor B ◽  
Age Related ◽  
Using Data

Objective: To investigate the potential correlation between complement factor B polymorphisms and age-related macular degeneration. Methods: We retrieved relevant articles systematically by searching PubMed and Web of Science databases. The pooled odds ratios and 95% confidence intervals were calculated for five complement factor B polymorphism rs641153, rs4151667, rs1048709, rs2072633, and rs12614 using data from included articles in both random effects and fixed effect models. Subgroup meta-analysis based on age-related macular degeneration type, choroidal neovascular disease (rs641153 and rs4151667), geographic atrophy (rs641153 and rs4151667), and races was also performed. Results: In the overall comparison, we observed that the distribution of rs641153 and the risk of age-related macular degeneration were significantly correlated (p < 0.00001). Similar results were obtained in subgroup analysis based on race (Caucasians, p < 0.00001; Asians, p = 0.003) and age-related macular degeneration type (choroidal neovascular disease, p < 0.00001; geographic atrophy, p = 0.04). As for complement factor B rs4151667, the genotypic effects were also demonstrated statistically significant in overall analysis (p < 0.00001) and only in Caucasians diagnosed with choroidal neovascular disease (p = 0.004), but not in Asians. Moreover, no statistically significant correlations between the complement factor B polymorphisms rs1048709 (p = 0.63), rs2072633 (p = 0.72), rs12614 (p = 0.98) and susceptibility to age-related macular degeneration were detected in either overall or subgroup analysis. Conclusion: Collectively, we demonstrated that the complement factor B genes rs641153 and rs4151667, but not rs1048709, rs2072633, rs12614, were associated with the susceptibility of age-related macular degeneration and might play predictive roles in future age-related macular degeneration diagnosis. More studies are needed to verify these findings.

scholarly journals Association of imaging biomarkers and local activation of complement in aqueous humor of patients with early forms of age-related macular degeneration

2020 ◽  
Author(s):  
Vasilena Sitnilska ◽  
Philip Enders ◽  
Claus Cursiefen ◽  
Sascha Fauser ◽  
Lebriz Altay
Keyword(s):  
Macular Degeneration ◽  
Aqueous Humor ◽  
Complement Activation ◽  
Rank Correlation ◽  
Age Related Macular Degeneration ◽  
Imaging Biomarkers ◽  
Complement Factor ◽  
Complement Protein ◽  
Complement Factors ◽  
Age Related

Abstract Purpose To investigate a possible correlation between established imaging biomarkers for age-related macular degeneration and local complement system activation, measured in aqueous humor (AH) of patients with early stages of age-related macular degeneration (AMD) and controls. Methods This analysis included prospectively acquired AH samples of 106 eyes (35 with early/intermediate AMD, 71 controls). The levels of complement protein 3 (C3), 4 (C4), 5 (C5); activation products of complement factor 3a (C3a) and Ba, C3b/iC3b; complement factors B, D, H, I (CFB, CFD, CFH, CFI); and total protein concentration were analyzed. Quantitative levels of complement factors were correlated to the presence of reticular pseudodrusen (RPD), the presence of hyperreflective foci (HRF), and total drusen volume (DV) graded on imaging by spectral-domain optical coherence tomography and using Spearman’s rank correlation test. Results DV correlated with C3b/iC3b (r = 0.285; P = 0.034), C3a (r = 0.200; P = 0.047), Ba (r = 0.262; P = 0.009), and C5 (r = 430; P = 0.005), and showed a tendency towards correlation with C3a (r = 0.198; P = 0.057). HRF correlated significantly with C5 (r = 0.388; P = 0.011) and RPD showed a tendency towards correlation with CFB (r = 0.196; P = 0.050). Conclusion In patients with early AMD, HRF and drusen parameters but not RPD show low to fair levels of correlation with local complement activation in patients’ AH. Better understanding of complement activation could provide some insights into the pathogenesis of AMD. Imaging biomarkers could be useful to identify suitable patients for future clinical trials with complement-modulating therapies.

scholarly journals Systemic Complement Inhibition with Eculizumab for Geographic Atrophy in Age-Related Macular Degeneration

Ophthalmology ◽  
2014 ◽  
Vol 121 (3) ◽  
pp. 693-701 ◽  
Author(s):  
Zohar Yehoshua ◽  
Carlos Alexandre de Amorim Garcia Filho ◽  
Renata Portella Nunes ◽  
Giovanni Gregori ◽  
Fernando M. Penha ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Complement Inhibition ◽  
Age Related

scholarly journals Electrophysiological signs of retinal cone remodeling in geographic atrophy of the pigment epithelium in patients with non-exudative age-related macular degeneration

2021 ◽  
Vol 14 (3) ◽  
pp. 32-39
Author(s):  
N. V. Neroeva ◽  
M. V. Zueva ◽  
V. V. Neroev ◽  
I. V. Tsapenko ◽  
M. V. Ryabina ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Selective Reduction ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Fundus Photography ◽  
Exudative Amd ◽  
Age Related ◽  
Retinal Cone

Testing patients with primary geographic atrophy (GA) requires a multimodal approach and identification of functional biomarkers characterizing retinal structural remodeling.Purpose: to identify the changes in the functional activity of the retinal cone system, which may serve as biomarkers of primary GA in non-exudative age-related macular degeneration (AMD).Material and methods. We tested 22 patients (30 eyes) aged 45–83 (ave. 72.1 ± 10.8 years) with non-exudative AMD and 18 age matched controls (60.2 ± 7.6 years) all of which underwent standard ophthalmological examinations, optical coherence tomography, autofluorescence study, and fundus photography. Standard photopic ERGs, photopic flicker ERGs to stimuli with frequencies of 8.3, 10, 12, and 24 Hz, multifocal ERG (mfERG), and electrooculogram (EOG) were recorded.Results. Electroretinographic signs for GA of retinal pigment epithelium and choriocapillary layer atrophy were described. The results confirm early impairment of the activity of cones in GA and weakening of the functional interaction of M ller cells with the cone bipolar cells. The delayed P1 peak latency of mfERG indicates a decrease in the entire central retina function in non-exudative AMD. A selective reduction in the fovea's mfERG magnitude can serve as a biomarker of primary GA. The spread of the P1 anomaly to adjacent rings may indicate a possible risk of disease progression. A decrease in the dark trough on the EOG and an increase in the Arden ratio can serve as a biomarker of primary GA.Conclusion. We determined electrophysiological signs which can serve as markers of early retinal dysfunction in eyes with primary GA and non-exudative AMD.

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