The dry (atrophic) form of age-related macular degeneration (AMD) is a slowly progressing neurodegenerative disorder in which specialized neurons (rod and cone photoreceptors) die in the central part of the retina called the macula. AMD is the most common cause of legal blindness in individuals aged 60 years and older. In the US, an estimated 15 million Americans suffer with dry AMD. Notably, the number of Americans afflicted with AMD is expected to double to 22 million by 2050 while the global patient population is expected to swell to 288 million by the year 2040. 

Dry AMD is a multifactorial disease with multiple genetic correlations and environmental/lifestyle stressors contributing to disease incidence and pathophysiology. Underlying drivers of disease pathophysiology include inflammation/complement system dysregulation and excessive buildup of retinal bisretinoids.Two therapies have been recently approved for dry AMD treatment: pegcetacoplan, a peptidic C3 complement inhibitor and avacincaptad pegol, a PEGylated RNA aptamer that inhibits complement component C5. However, their effectiveness is minimal, frequent intraocular injections are required, and there are concerns about inducing a more severe form of neovascular AMD in patients treated with both drugs. Thus, the discovery and development of novel drug therapies for dry AMD remains a critical unmet need. 

Photoreceptor loss in dry AMD is secondary to abnormalities in the Retinal Pigment Epithelium (RPE), a cellular layer that provides metabolic support to rods and cones. In dry AMD, age-dependent accumulation of lipofuscin in the RPE correlates with age-related increased incidences of the disease and represents one of several pathogenic factors contributing to the disease onset and progression. Bisretinoids, a byproduct of the visual cycle stemming from retinaldehyde dimerization, mediate lipofuscin toxicity and exert a variety of deleterious effects on RPE cells. Among them is the dysregulation of the complement system and inflammasome activation, the hallmarks of dry AMD pathology. Retinaldehyde toxicity may have an independent role in the disease pathology.