The role of DICER1 in neovascular AMD

Age related macular degeneration (AMD) is a leading cause of irreversible blindness in industrialized nations, affecting 1.8 million individuals in the United States alone. There are two primary forms of the disease: the “wet” form that is marked by blood vessels intrusion into the retina, and the more common “dry” form of the disease does not have blood vessels aberrantly intruding into the eye. It is not currently understood how dry AMD progresses into wet AMD in some patients but not others, but a hypothesized link between the two forms of the disease is supported by reports showing that patients with wet AMD treated with anti-vascular endothelial growth factor A (VEGF-A) therapies develop dry AMD at high rates. Our laboratory recently found that DICER1 deficiency resulted in Alu RNA accumulation in the eyes of patients with advanced dry AMD and that the RPE is responsible for synthesizing soluble VEGF receptor 1 (sFLT-1), which shields photoreceptors in the overlying retina from intruding vascular growth. We have preliminary data showing that subretinal administration of Alu RNA to wild type mouse eyes can exacerbate laser-induced choroidal neovascularization (CNV) and other that a mouse line carrying a hypomorphic DICER1 mutation (d/d) develops RPE degeneration and CNV with age. I propose to investigate whether DICER1 deficiency reduces sFLT-1 expression independently of RPE cell death and will test in cell culture if DICER1 antisense can induce lower expression of sFLT-1 and induce higher expression of VEGF-A. I will also examine d/d mice for reduced sFLT-1 expression and increased VEGF-A expression. This proposed research avenue will provide insight into how dry and wet AMD are related.