Interactions of Immune Proteins and Glucose Breakdown in Severe, Hereditary AMD

Early onset macular drusen (EOMD) is an inherited, severe form of AMD. We found that retinal pigmented epithelium (RPE) cells made from EOMD patients have decreased (~50%) expression of two important complement proteins, CFH and FHL-1. This significant decrease may alter local complement activity and RPE metabolism. We will study EOMD patient RPE, and their gene-edited controls, and determine whether adding the FHL-1 gene back to the EOMD cells will help attenuate these pathogenic changes. This project will help our understanding of AMD disease pathogenesis and treatment.

We will culture induced pluripotent stem cell-derived RPE cells from patients with a rare CFH variant that results in reduced CFH and FHL-1 protein production. In Aim 1, we will investigate the RPE extracellular complement activity and intracellular complosome. FHL-1 will be supplemented via AAV-mediated transduction to determine FHL-1 sufficiency to the local complement activity in the RPE. In Aim 2, we will evaluate if altered CFH and FHL-1 levels affects glucose metabolism and glycosaminoglycan synthesis in the RPE, and whether supplemental FHL-1 expression can attenuate these changes.

This study employs patient-specific RPE with a novel CFH mutation that perturbs the complement pathway, therefore allowing for in-depth examination of the complement system during AMD-like conditions. Moreover, the connection between the heightened extracellular complement activity and its effects on intracellular glucose metabolism has not yet been studied in the RPE.

Success of this study will uncover the therapeutic potential and mechanism of action for FHL-1 in the treatment of early AMD. The relatively small size of FHL-1 permits easy packaging for delivery into the RPE.