Chinchilla Rodríguez, BlancaFoltopoulou, ParthenaFernandez Godino, Rosario2025-01-282025-01-282021-07-27Chinchilla, 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.57470022-341710.1002/path.5747https://hdl.handle.net/20.500.14352/116680Despite 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.engjournal article1096-9896https://doi.org/10.1002/path.574734155630restricted access636.09:612.017Tick-overComplementRetinal pigment epitheliumBasal depositsAge-related macular degenerationInmunología veterinaria3109.03 Inmunología