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C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration

Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is a retinal neurodegenerative disorder. Human genetic data support the complement system as a key component of pathogenesis in AMD, which has been further supported by pre-clinical and recent clinical studies. However, the...

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Autores principales: Yednock, Ted, Fong, Donald S., Lad, Eleonora M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9641935/
https://www.ncbi.nlm.nih.gov/pubmed/36348407
http://dx.doi.org/10.1186/s40942-022-00431-y
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author Yednock, Ted
Fong, Donald S.
Lad, Eleonora M.
author_facet Yednock, Ted
Fong, Donald S.
Lad, Eleonora M.
author_sort Yednock, Ted
collection PubMed
description Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is a retinal neurodegenerative disorder. Human genetic data support the complement system as a key component of pathogenesis in AMD, which has been further supported by pre-clinical and recent clinical studies. However, the involvement of the different complement pathways (classical, lectin, alternative), and thus the optimal complement inhibition target, has yet to be fully defined. There is evidence that C1q, the initiating molecule of the classical pathway, is a key driver of complement activity in AMD. C1q is expressed locally by infiltrating phagocytic cells and C1q-activating ligands are present at disease onset and continue to accumulate with disease progression. The accumulation of C1q on photoreceptor synapses with age and disease is consistent with its role in synapse elimination and neurodegeneration that has been observed in other neurodegenerative disorders. Furthermore, genetic deletion of C1q, local pharmacologic inhibition within the eye, or genetic deletion of downstream C4 prevents photoreceptor cell damage in mouse models. Hence, targeting the classical pathway in GA could provide a more specific therapeutic approach with potential for favorable efficacy and safety.
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spelling pubmed-96419352022-11-15 C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration Yednock, Ted Fong, Donald S. Lad, Eleonora M. Int J Retina Vitreous Review Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is a retinal neurodegenerative disorder. Human genetic data support the complement system as a key component of pathogenesis in AMD, which has been further supported by pre-clinical and recent clinical studies. However, the involvement of the different complement pathways (classical, lectin, alternative), and thus the optimal complement inhibition target, has yet to be fully defined. There is evidence that C1q, the initiating molecule of the classical pathway, is a key driver of complement activity in AMD. C1q is expressed locally by infiltrating phagocytic cells and C1q-activating ligands are present at disease onset and continue to accumulate with disease progression. The accumulation of C1q on photoreceptor synapses with age and disease is consistent with its role in synapse elimination and neurodegeneration that has been observed in other neurodegenerative disorders. Furthermore, genetic deletion of C1q, local pharmacologic inhibition within the eye, or genetic deletion of downstream C4 prevents photoreceptor cell damage in mouse models. Hence, targeting the classical pathway in GA could provide a more specific therapeutic approach with potential for favorable efficacy and safety. BioMed Central 2022-11-08 /pmc/articles/PMC9641935/ /pubmed/36348407 http://dx.doi.org/10.1186/s40942-022-00431-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Review
Yednock, Ted
Fong, Donald S.
Lad, Eleonora M.
C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration
title C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration
title_full C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration
title_fullStr C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration
title_full_unstemmed C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration
title_short C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration
title_sort c1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9641935/
https://www.ncbi.nlm.nih.gov/pubmed/36348407
http://dx.doi.org/10.1186/s40942-022-00431-y
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