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Complement factor B is critical for sub-RPE deposit formation in a model of DHRD/ML with features of age-related macular degeneration

Crowley, Maura, Garland, Donita, Sellner, Holger, Banks, Angela, Rejtar, Tomas, Buchanan, Natasha, Delgado, Omar, Xu, YongYao, Adams, Christopher, Mogi, Muneto, Bigelow, Chad, Poor, Stephen, Anderson, Karen, Jaffee, Bruce, Prasanna, Ganesh, Grosskreutz, Cyndy, Feenandez-Godino, Rosario, Pierce, Eric, Dryja, Thaddeus and Liao, Sha-Mei (2022) Complement factor B is critical for sub-RPE deposit formation in a model of DHRD/ML with features of age-related macular degeneration. Human molecular genetics.


EFEMP1 R345W is a protein misfolding-prone mutation causing Doyne honeycomb retinal dystrophy/Mallatia Leventinese (DHRD/ML), a rare blinding disease with similar clinical pathology to a common disease of age-related macular degeneration (AMD). Aged Efemp1R345W/R345W knock-in mice (Efemp1ki/ki mice) develop deposits on the basal side of retinal pigment epithelial cells, which is complement C3- dependent. We assessed alternative complement pathway component factor B (FB) in sub-RPE deposit formation in Efemp1ki/ki mice. RNA-seq analysis of Efemp1ki/ki mice comparing to Efemp1+/+ reveals increased unfolded protein response in posterior eye cups, decreased mitochondrial function in neural retina (both by 3-month-old), and increased inflammatory pathways in both tissues (at 17-month-old). Aged Efemp1ki/ki mice also exhibits elevated ocular complement protein activation with around two-fold (p<0.05) elevation of breakdown products iC3b and Ba by Western blot analysis. Proteomics analysis of eye lysate confirmed similar Efemp1 R345W-dysregulated pathways as detected by RNA-seq. Cfb deficiency partially normalizes these biological pathway changes in the eyes of female Efemp1ki/ki mice. Female Efemp1ki/ki mice dosed with a small molecule FB inhibitor from 10- to 12-month-old reduced sub-RPE deposits by 65% (p=0.051). Male Efemp1ki/ki mice had fewer sub-RPE deposits than age-matched females and no elevation of ocular complement activation, therefore not affected by FB inhibitor. Sub-RPE deposits/drusen, seen in Efemp1ki/ki mice, are a common early clinical feature of DHRD/ML and AMD. The broader effect on Efemp1ki/ki mice by either Cfb deficiency or oral FB inhibition suggest that systemic inhibition of the alternative complement pathway is potentially an effective strategy for treatment of dry AMD and DHRD/ML.

Item Type: Article
Date Deposited: 24 Jan 2023 00:45
Last Modified: 24 Jan 2023 00:45