Patient and Retinal Region-Specific iPSC-Derived RPE Models to Study AMD

We aim to understand the differential sensitivity of central and peripheral retinal pigment epithelium (RPE) to age-related macular degeneration. The first goal of this project is to recreate and functionally validate the central and peripheral RPE subpopulations in a dish using patient-specific stem cells. We will identify the molecular and physiological differences between the two subpopulations. The second goal is to discover signaling pathways that make the central RPE more vulnerable to AMD as compared to the peripheral RPE.

Two hundred and forty million people, globally, are estimated to lose vision in the next 20 years due to Age-related Macular Degeneration (AMD). AMD is a disease of the central retina, which affects people starting in the sixth decade of life and causes socio-economic burden. Vision loss in advanced stages of the disease is initiated by the death of the retinal pigment epithelium (RPE), a monolayer of cells that supports light-sensing photoreceptor cells of the retina. RPE loss is seen in the center of the retina, but not in the periphery. We discovered the existence of distinct central and peripheral RPE populations and hypothesize that those two populations are differentially vulnerable to AMD. In this project, we aim to recreate the central and peripheral RPE populations in a dish, using patient-specific stem cells, and study why the central population dies more easily when we simulate the environmental factors that initiate AMD. We will identify molecular and physiological differences between the two populations generated in a dish and we will find which properties make the central RPE more vulnerable than peripheral RPE. Our RPE model is easily reproducible and will be used by other researchers to answer specific questions regarding AMD. Understanding what makes central RPE more vulnerable than peripheral RPE, plus having an easily reproducible model in a dish, will eventually translate in the development of drugs to prevent vision loss caused by AMD.

AMD affects mainly the central region of the retina and the RPE. Currently, there is no cell culture model to study resilience of peripheral RPE cells or sensitivity of central RPE cells in AMD. Generating the first cellular model of central and peripheral RPE is the most innovative aspect of this proposal.

The central and peripheral RPE models will be easily reproducible by other researchers in the field, who will used them to address specific questions about AMD and other retinal degenerative diseases. The model will also help us understand what makes central RPE more vulnerable than peripheral RPE. All this will eventually translate in the development of specific drugs to prevent vision loss caused by AMD.