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

Qin, Shuqi; Dong, Ning; Yang, Ming; Wang, Jialin; Xue, Feng; Wang, Yanling

doi:10.1155/2021/9945725

Cited by 22 publications

(28 citation statements)

References 130 publications

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“…Our data identified multiple complement genes expressed under normal physiological conditions that must have biological functions that maintain integrity of the retina, RPE and choroid. Further studies are necessary to investigate complement function for its role in homeostasis to provide a foundation for AMD clinical trials evaluating treatment with complement inhibitors [reviewed in ( 36 – 38 )].…”

Section: Discussionmentioning

confidence: 99%

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As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues

Zauhar

Biber²,

Jabri³

et al. 2022

Front. Immunol.

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The cellular events that dictate the initiation of the complement pathway in ocular degeneration, such as age-related macular degeneration (AMD), is poorly understood. Using gene expression analysis (single cell and bulk), mass spectrometry, and immunohistochemistry, we dissected the role of multiple retinal and choroidal cell types in determining the complement homeostasis. Our scRNA-seq data show that the cellular response to early AMD is more robust in the choroid, particularly in fibroblasts, pericytes and endothelial cells. In late AMD, complement changes were more prominent in the retina especially with the expression of the classical pathway initiators. Notably, we found a spatial preference for these differences. Overall, this study provides insights into the heterogeneity of cellular responses for complement expression and the cooperation of neighboring cells to complete the pathway in healthy and AMD eyes. Further, our findings provide new cellular targets for therapies directed at complement.

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Section: Discussionmentioning

confidence: 99%

“…Recent clinical trials have utilized drugs to delay AMD progression through alteration of the complement pathway (reviewed in [ 36 – 38 )]. C3 inhibitors have received the most attention due to the dominant role of C3 as a control point for all three complement pathways.…”

Section: Introductionmentioning

confidence: 99%

As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues

Zauhar

Biber²,

Jabri³

et al. 2022

Front. Immunol.

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“…ANX007 (Annexon Inc., Brisbane, CA, USA) is a recombinant monoclonal antibody with an antigen-binding fragment that inhibits c1q. Through its action on c1q, the classical complement pathway is inhibited alongside C3 and C5 [ 60 , 61 ]. In a murine model of retinal photooxidative damage, ANX-M1, a monoclonal anti-C1q antibody similar to ANX007, reduced retinal atrophy [ 62 ].…”

Section: Current Therapeutic Targetsmentioning

confidence: 99%

“…In a murine model of retinal photooxidative damage, ANX-M1, a monoclonal anti-C1q antibody similar to ANX007, reduced retinal atrophy [ 62 ]. Furthermore, a phase I trial (NCT04188015) using 2.5 mg and 5 mg of intravitreal (IVT) ANX007 demonstrated the safety and tolerability of both doses in 17 patients with primary open-angle glaucoma [ 60 , 61 ].…”

Section: Current Therapeutic Targetsmentioning

confidence: 99%

Targeting the Complement Cascade for Treatment of Dry Age-Related Macular Degeneration

Patel

Land

et al. 2022

Biomedicines

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Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the elderly population. AMD is characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). Regarding the latter type, there is growing evidence supporting an association between the pathophysiology of dry AMD and key proteins in the complement cascade. The complement cascade works as a central part of the innate immune system by defending against foreign pathogens and modified self-tissues. Through three distinct pathways, a series of plasma and membrane-associated serum proteins are activated upon identification of a foreign entity. Several of these proteins have been implicated in the development and progression of dry AMD. Potential therapeutic targets include C1q, C3, C5, complement factors (B, D, H, I), membrane attack complex, and properdin. In this review, we provide an understanding of the role of the complement system in dry AMD and discuss the emerging therapies in early phase clinical trials. The tentative hope is that these drugs may offer the potential to intervene at earlier stages in dry AMD pathogenesis, thereby preventing progression to late disease.

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“…Recently, the complement system has become a new therapeutic target for AMD, particularly its advanced forms. While complement inhibitors have up to now failed to treat AMD successfully, emerging gene therapy may offer new opportunities to treat AMD in the future [ 143 , 144 ]. Associations have been found between polymorphisms in the complement pathway and mtDNA damage of RPE in AMD.…”

Section: Choriocapillaris In Early Amdmentioning

confidence: 99%

Microbiota mitochondria disorders as hubs for early age-related macular degeneration

Fehér¹,

Élő

István

et al. 2022

GeroScience

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Age-related macular degeneration (AMD) is a progressive neurodegenerative disease affecting the central area (macula lutea) of the retina. Research on the pathogenic mechanism of AMD showed complex cellular contribution governed by such risk factors as aging, genetic predisposition, diet, and lifestyle. Recent studies suggested that microbiota is a transducer and a modifier of risk factors for neurodegenerative diseases, and mitochondria may be one of the intracellular targets of microbial signaling molecules. This review explores studies supporting a new concept on the contribution of microbiota—mitochondria disorders to AMD. We discuss metabolic, vascular, immune, and neuronal mechanism in AMD as well as key alterations of photoreceptor cells, retinal pigment epithelium (RPE), Bruch’s membrane, choriocapillaris endothelial, immune, and neuronal cells. Special attention was paid to alterations of mitochondria contact sites (MCSs), an organelle network of mitochondria, endoplasmic reticulum, lipid droplets (LDs), and peroxisomes being documented based on our own electron microscopic findings from surgically removed human eyes. Morphometry of Bruch’s membrane lipids and proteoglycans has also been performed in early AMD and aged controls. Microbial metabolites (short-chain fatty acids, polyphenols, and secondary bile acids) and microbial compounds (lipopolysaccharide, peptidoglycan, and bacterial DNA)—now called postbiotics—in addition to local effects on resident microbiota and mucous membrane, regulate systemic metabolic, vascular, immune, and neuronal mechanisms in normal conditions and in various common diseases. We also discuss their antioxidant, anti-inflammatory, and metabolic effects as well as experimental and clinical observations on regulating the main processes of photoreceptor renewal, mitophagy, and autophagy in early AMD. These findings support an emerging concept that microbiota-mitochondria disorders may be a crucial pathogenic mechanism of early AMD; and similarly, to other age-related neurodegenerative diseases, new treatment approaches should be targeted at these disorders.

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

Cited by 22 publications

References 130 publications

As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues

As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues

Targeting the Complement Cascade for Treatment of Dry Age-Related Macular Degeneration

Microbiota mitochondria disorders as hubs for early age-related macular degeneration

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