C1q inhibition protects photoreceptor synapses and preserves retinal function in a preclinical model of photoreceptor degeneration

Abstract

Purpose : Geographic atrophy (GA) is an advanced form of age-related macular degeneration leading to photoreceptor death and visual loss. Increased expression of complement components has been observed in retinal tissue from GA patients. The role of C1q and the classical complement pathway in driving disease progression is under investigation.

We hypothesize that C1q plays a pathogenic role in GA by tagging synapses on stressed photoreceptors in the outer plexiform layer (OPL), driving microglial cell-mediated synapse pruning and inflammation.

In this study, we examined complement expression and C1q tissue localization in the retina of a photo-oxidative light damage model of photoreceptor degeneration and determined the potential therapeutic benefit of classical complement inhibition.

Methods : BALB/c mice were exposed to white light to cause retinal damage and were observed at Days 1, 3 and 7 post-light exposure. Classical complement component levels were measured in retinal lysates by ELISA. C1q expression in tissue was assessed by immunohistochemistry. Microglial engulfment of synapses was assessed using IMARIS software. To assess the role of the classical complement pathway in photoreceptor cell damage, C1q activity was pharmacologically blocked by intravitreal injection of a C1q-inhibiting antibody. Retina specimens from GA patients were procured from the San Diego Eye Bank.

Results : Using a light-induced damage model of photoreceptor degeneration in mice, we provide the first time evidence of C1q deposition on photoreceptor synapses, followed by microglial cell recruitment and synapse engulfment. We demonstrate that pharmacological inhibition of C1q protects photoreceptor synapses and preserves retinal function following exposure to damaging light. Finally, we demonstrate the relevance of this process to human disease with the first time evidence of C1q deposition on photoreceptor synapses in postmortem human GA retinas outside areas of atrophy and a gradient of photoreceptor synapse and cell loss above intact retinal pigment epithelium nearing the lesion edge.

Conclusions : These results support a role of C1q in the pathogenic elimination of photoreceptor cell synapses and, importantly, provide mechanistic understanding of recent phase 2 clinical findings showing protection against vision loss in GA with anti-C1q treatment (NCT04656561).

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