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Implications of genetic variation in the complement system in age-related macular degeneration.
Prog Retin Eye Res. 2021 Feb 19 [Online ahead of print]PR

Abstract

Age-related macular degeneration (AMD) is the main cause of vision loss among the elderly in the Western world. While AMD is a multifactorial disease, the complement system was identified as one of the main pathways contributing to disease risk. The strong link between the complement system and AMD was demonstrated by genetic associations, and by elevated complement activation in local eye tissue and in the systemic circulation of AMD patients. Several complement inhibitors have been and are being explored in clinical trials, but thus far with limited success, leaving the majority of AMD patients without treatment options to date. This indicates that there is still a gap of knowledge regarding the functional implications of the complement system in AMD pathogenesis and how to bring these towards clinical translation. Many different experimental set-ups and disease models have been used to study complement activation in vivo and in vitro, and recently emerging patient-derived induced pluripotent stem cells and genome-editing techniques open new opportunities to study AMD disease mechanisms and test new therapeutic strategies in the future. In this review we provide an extensive overview of methods employed to understand the molecular processes of complement activation in AMD pathogenesis. We discuss the findings, advantages and challenges of each approach and conclude with an outlook on how recent, exciting developments can fill in current knowledge gaps and can aid in the development of effective complement-targeting therapeutic strategies in AMD.

Authors+Show Affiliations

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands.Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands.Department of Human Genetics, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Department of Pediatrics, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Amalia Children's Hospital, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands.Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands.Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands.Gemini Therapeutics Inc., Cambridge, MA, 02139, USA.Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Amalia Children's Hospital, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Department of Laboratory Medicine, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands.Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Amalia Children's Hospital, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Department of Laboratory Medicine, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands.Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands. Electronic address: anneke.denhollander@radboudumc.nl.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

33610747

Citation

de Jong, Sarah, et al. "Implications of Genetic Variation in the Complement System in Age-related Macular Degeneration." Progress in Retinal and Eye Research, 2021, p. 100952.
de Jong S, Gagliardi G, Garanto A, et al. Implications of genetic variation in the complement system in age-related macular degeneration. Prog Retin Eye Res. 2021.
de Jong, S., Gagliardi, G., Garanto, A., de Breuk, A., Lechanteur, Y. T. E., Katti, S., van den Heuvel, L. P., Volokhina, E. B., & den Hollander, A. I. (2021). Implications of genetic variation in the complement system in age-related macular degeneration. Progress in Retinal and Eye Research, 100952. https://doi.org/10.1016/j.preteyeres.2021.100952
de Jong S, et al. Implications of Genetic Variation in the Complement System in Age-related Macular Degeneration. Prog Retin Eye Res. 2021 Feb 19;100952. PubMed PMID: 33610747.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Implications of genetic variation in the complement system in age-related macular degeneration. AU - de Jong,Sarah, AU - Gagliardi,Giuliana, AU - Garanto,Alejandro, AU - de Breuk,Anita, AU - Lechanteur,Yara T E, AU - Katti,Suresh, AU - van den Heuvel,Lambert P, AU - Volokhina,Elena B, AU - den Hollander,Anneke I, Y1 - 2021/02/19/ PY - 2020/11/30/received PY - 2021/02/08/revised PY - 2021/02/11/accepted PY - 2021/2/22/pubmed PY - 2021/2/22/medline PY - 2021/2/21/entrez KW - Age-related macular degeneration KW - Clinical trials KW - Complement system KW - Genetic variants KW - Model systems SP - 100952 EP - 100952 JF - Progress in retinal and eye research JO - Prog Retin Eye Res N2 - Age-related macular degeneration (AMD) is the main cause of vision loss among the elderly in the Western world. While AMD is a multifactorial disease, the complement system was identified as one of the main pathways contributing to disease risk. The strong link between the complement system and AMD was demonstrated by genetic associations, and by elevated complement activation in local eye tissue and in the systemic circulation of AMD patients. Several complement inhibitors have been and are being explored in clinical trials, but thus far with limited success, leaving the majority of AMD patients without treatment options to date. This indicates that there is still a gap of knowledge regarding the functional implications of the complement system in AMD pathogenesis and how to bring these towards clinical translation. Many different experimental set-ups and disease models have been used to study complement activation in vivo and in vitro, and recently emerging patient-derived induced pluripotent stem cells and genome-editing techniques open new opportunities to study AMD disease mechanisms and test new therapeutic strategies in the future. In this review we provide an extensive overview of methods employed to understand the molecular processes of complement activation in AMD pathogenesis. We discuss the findings, advantages and challenges of each approach and conclude with an outlook on how recent, exciting developments can fill in current knowledge gaps and can aid in the development of effective complement-targeting therapeutic strategies in AMD. SN - 1873-1635 UR - https://www.unboundmedicine.com/medline/citation/33610747/Implications_of_genetic_variation_in_the_complement_system_in_age-related_macular_degeneration. L2 - https://linkinghub.elsevier.com/retrieve/pii/S1350-9462(21)00013-6 DB - PRIME DP - Unbound Medicine ER -
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