Dry-Age Related Macular Degeneration is the only major ophthalmic disease with no approved treatment and is one of most common causes of vision loss world-wide. The most severe form of dry AMD is geographic atrophy (GA), which affects an estimated 1 million people in the US. At this stage of the disease, patches of a layer of the retina (the retinal pigmented epithelium) die, causing death of the overlying sensory retina and vision loss. Causes of dry AMD/GA are not fully understood, but it is associated with age, smoking, and genetics.
As dry AMD develops, fatty deposits called drusen accumulate under the retina within which are found deposits of amyloid-β (the same protein found in Alzheimer’s disease brains), components of the immune modulating complement family (including C3, C5, and Factor D) and Alu RNA, a toxic RNA molecule. These stressors activate inflammasomes in cells of the retina, which in turn cause maturation and release of the inflammatory cytokines IL-1β and IL-18. In some cases, VEGF is subsequently produced leading to the development of wet AMD. In other cases, RPE and retinal cells die. Larger patches of dead RPE and retina then form and expand, giving rise to GA. In some cases, patients have both wet AMD and GA. This is becoming more common, possibly because GA is being detected more easily or because anti-VEGF injections for wet AMD are accelerating the development of GA. It is now recognized that inflammasome activation is a key point of convergence in the development of both GA and wet AMD.