Recombinant human complement factor H CPV-101 and CPV-104 dampen microglia reactivity and attenuate light-induced retinal degeneration

Abstract

Purpose : AMD is a complex, heterogeneous and progressive chronic disease of the central retina that leads to severe vision loss among the elderly in the western world. Several lines of evidence including genome-wide association studies and preclinical model systems implicate microglia reactivity and dysregulated complement system in the pathogenesis of AMD. Genetic variants of complement factor H (CFH), an important regulator of the alternative pathway, are among the most prevalent polymorphisms that are associated with increased AMD risk. Here, we investigated whether moss-derived recombinant human CFH variants: CPV-101 and CPV-104 have immunomodulatory and neuroprotective functions in a mouse model of light-induced retinal degeneration.

Methods : BALB/cJ mice received intravitreally injections of 5µg CFH CPV-101 and CPV-104 or vehicle, starting 1 day prior to exposure to 10,000 lux white light for 30 min. The effects of CPV-101 and CPV-104 treatment on microglia and Müller cell reactivity were analyzed by immunostainings of retinal sections and flat mounts and gene expression of microglia markers using quantitative real-time PCR (qRT-PCR). Optical coherence tomography (OCT); Blue Peak Autofluorescence (BAF); terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stainings, and morphometric analyses were used to quantify the extent of retinal degeneration and photoreceptor apoptosis.

Results : Light-exposed mice treated with recombinant CFH CPV-101 or CPV-104 showed strongly decreased microglia and Müller cell reactivity concomitantly with reduced pro-inflammatory cytokines compared to vehicle controls. Furthermore, light-induced retinal degeneration was attenuated in mice that received CPV-101 or CPV-104.

Conclusions : Moss-derived recombinant human CFH CPV-101 and CPV-104 counter-regulates microgliosis and attenuates light-induced retinal degeneration, highlighting a promising concept for the treatment of AMD patients.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.