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Tick‐over‐mediated complement activation is sufficient to cause basal deposit formation in cell‐based models of macular degeneration
Author(s) -
Chinchilla Blanca,
Foltopoulou Parthena,
FernandezGodino Rosario
Publication year - 2021
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5747
Subject(s) - drusen , macular degeneration , retinal pigment epithelium , downregulation and upregulation , complement system , complement membrane attack complex , microbiology and biotechnology , biology , cell , retinal , immunology , cancer research , medicine , gene , ophthalmology , genetics , biochemistry , immune system
Despite numerous unsuccessful clinical trials for anti‐complement drugs to treat age‐related macular degeneration (AMD), the complement system has not been fully explored as a target to stop drusen growth in patients with dry AMD. We propose that the resilient autoactivation of C3 by hydrolysis of its internal thioester (tick‐over), which cannot be prevented by existing drugs, plays a critical role in the formation of drusenoid deposits underneath the retinal pigment epithelium (RPE). We have combined gene editing tools with stem cell technology to generate cell‐based models that allow the role of the tick‐over in sub‐RPE deposit formation to be studied. The results demonstrate that structurally or genetically driven pathological events affecting the RPE and Bruch's membrane can lead to dysregulation of the tick‐over, which is sufficient to stimulate the formation of sub‐RPE deposits. This can be prevented with therapies that downregulate C3 expression. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.