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 examined expression and tissue localization of complement proteins in the retina of mice exposed to light damage and determined the potential therapeutic benefit of classical complement inhibition in this model.
Methods :
Balb/c mice were exposed to white light to cause retinal damage and observed at Day 1, 3 and 7 post light exposure. Classical complement component levels were measured in retina lysates by ELISA. C1q expression in the tissue was assessed by IHC. Microglia engulfment of synapses was assessed using IMARIS software. To test the role of the classical complement pathway in photoreceptor cell damage, C1q activity was pharmacologically blocked by intravitreal injection of a C1q inhibitory antibody. Retina specimens from GA patients were procured from the San Diego Eye Bank.
Results :
There was progressive loss of photoreceptor synapses and cell bodies, as well as an increase in microglial cells across the outer plexiform (OPL, synapses) and outer nuclear layers (ONL, cell bodies) in mice exposed to light damage. C1q expression was induced in microglia and was localized on photoreceptor synapses and cell bodies following light damage. There was a significant correlation between levels of C1q in the OPL and ONL and photoreceptor synapse and cell body loss. C1q-tagged synapses were engulfed by microglial cells upon damage suggesting a causal relationship. Treatment with a C1q inhibitory antibody normalized complement component levels. Preliminary evidence showed reduced photoreceptor synapse and cell body loss, and reduced inflammation. We confirmed C1q deposition on photoreceptor synapses in human GA retina tissue suggesting that this mechanism may be operative in humans.
Conclusions :
We provide first evidence of C1q deposition on photoreceptor synapses in a light exposure model of retinal damage in mice and in human GA tissue. Preliminary results suggest that inhibiting C1q protects against photoreceptor neuron damage. A Phase 2 study with a C1q inhibitory antibody is ongoing in GA patients (clinical trials.gov NCT04656561).
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.