Human primary and induced pluripotent stem cell-derived (iPSC) RPE culture models of dry macular degeneration; autophagy; RPE lipid biology and metabolism

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. The disease comes in two forms - a slowly progressive degeneration called dry AMD and a much more rapidly progressive degeneration involving abnormal blood vessel growth called wet AMD. Starting in approximately 2005, anti-blood vessel medications have led to a radical improvement in our ability to save vision in wet AMD patients. However, for the 80+% of patients with dry AMD, we lack any proven therapeutic intervention. We study the mechanisms driving dry AMD with the goal of identifying therapeutics for this disease.

Macular degeneration affects the retina, the layers of cells in the back of the eye that turn light into electrical signals that the brain can interpret. Humans and primates are unique in the structure and properties of their retina, and it has therefore been difficult to establish non-primate animal models of AMD that truly recapitulate all features of the disease. We therefore seek to use cells that we collect from human retinas to build a model of AMD in a culture dish. The cells most affected in macular degeneration come from a pigmented layer of the retina called the retinal pigment epithelium (RPE). Our experiments involve stressing human RPE grown in the lab with a range of insults (including the insult of just carrying out routine daily activities but over a prolonged period of time), testing whether the RPE responds to the stress in a way that looks like the human disease. In particular, the cells on top of the RPE, called photoreceptors, undergo a daily shedding of their cell tips. These jettisoned fatty debris are cleared each day by the RPE. At the same time, lipid complexes enter the RPE from a set of tiny blood vessels underneath the RPE, called the choroid. These two lipid sources, photoreceptor tips and lipid particles from the blood stream, are an enormous burden to the RPE. Indeed, when the RPE loses its ability to efficiently clear this lipid load, the debris can accumulate outside the RPE as "cellular trash," a first sign of dry AMD. This trash is called "drusen."