%0 Journal Article
%A Chinchilla Rodríguez, Blanca
%A Foltopoulou, Parthena
%A Fernandez Godino, Rosario
%T Tick-over-mediated complement activation is sufficient to cause basal deposit formation in cell-based models of macular degeneration
%D 2021
%@ 0022-3417
%U https://hdl.handle.net/20.500.14352/116680
%X 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 can not 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.
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