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oai:docta.ucm.es:20.500.14352/1166802025-01-29T01:07:06Zcom_20.500.14352_14col_20.500.14352_15

Chinchilla Rodríguez, Blanca Foltopoulou, Parthena Fernandez Godino, Rosario 2025-01-28T16:33:55Z 2025-01-28T16:33:55Z 2021-07-27 Chinchilla, B., Foltopoulou, P., & Fernandez-Godino, R. (2021). Tick-over-mediated complement activation is sufficient to cause basal deposit formation in cell-based models of macular degeneration. Journal of Pathology, 255(2), 120-131. https://doi.org/10.1002/PATH.5747 0022-3417 10.1002/path.5747 https://hdl.handle.net/20.500.14352/116680 1096-9896 https://doi.org/10.1002/path.5747 34155630 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. eng restricted access Tick-over-mediated complement activation is sufficient to cause basal deposit formation in cell-based models of macular degeneration journal article