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.

Abstract

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
URI:	https://oak.novartis.com/id/eprint/46918