Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease

The complement system, a key component of innate immunity, is necessary to maintain tissue homeostasis. In the eye, the retinal pigment epithelium (RPE) plays a major role in controlling the immune response through expression of various complement negative regulatory proteins (CRPs). Here we identify that inappropriate activation of the complement cascade plays a role in the pathogenesis of recessive Stargardt disease (STGD1). Using the STGD1 mouse model, we show that overexpression of the complement receptor 1-like protein y, a major murine CRP, reduces complement attack on the RPE and rescues both bisretinoid accumulation and photoreceptor degeneration. Our data demonstrate that STGD1 presents with dysregulation of the complement system as also has been proposed for age-related macular degeneration, supporting a common etiologic pathway.