Repurposing an orally available drug for the treatment of geographic atrophy.

purposeChronic oxidative stress and subacute inflammation have been implicated as causes of age-related macular degeneration (AMD). In this study, we tested whether an orally available 5-OH-tryptamine (5HT) 1a receptor agonist, xaliproden, could protect against retinal pigment epithelium (RPE) cell damage in culture and in a mouse model of geographic atrophy.

methodsParaquat was used to create mitochondrial oxidative stress in ARPE-19 cells, and tumor necrosis factor-α (TNF-α) was used to stimulate the production of inflammatory cytokines in these cells. The production of antioxidant proteins, metallothionein, and inflammatory cytokines was assayed with quantitative real-time PCR. Cell survival was analyzed with microscopy and a cell titer assay. Integrity of the RPE monolayer was determined by measuring the transepithelial electrical resistance (TEER) and with immunocytochemistry with zona occludens protein 1 (ZO-1) antibody. RPE atrophy was studied in mice deleted for Sod2 (the gene for mitochondrial superoxide dismutase) specifically in the RPE. The mice were treated orally with daily doses of xaliproden at 0.5 and 3 mg/kg for 4 months. The retinal structure was analyzed with spectral domain optical coherence tomography (SD-OCT) and with light and electron microscopy. Retinal function was assessed with full-field electroretinography (ERG) and with optokinetic measurements.

resultsXaliproden led to a dose-dependent increase in cell survival following treatment with paraquat. Synthesis of the antioxidant response genes NqO1, GSTM1, CAT, HO-1, and Nrf2 was increased in response to the drug, as was the zinc chaperone metallothionein. Treatment of cells with TNF-α led to increased production of IL-1β, IL-6, chemokine (C-C motif) ligand 20 (CCL20), and vascular endothelial growth factor (VEGF) by ARPE-19 cells, and this response was attenuated by treatment with xaliproden. TNF-α also led to a decrease in the TEER that was prevented by treatment with the 5HT1a agonist. Daily gavage with xaliproden at either dose induced the production of protective enzymes in the mouse retina, and treatment of the Sod2-deleted mice with the drug showed improved thickness of the outer nuclear layer and improved visual acuity relative to the control-treated mice. There was no significant difference in full-field scotopic ERG among the treatment groups, however. Vacuolization of the RPE and disorganization of the photoreceptor outer segments were reduced at both dose levels of xaliproden.

conclusionsXaliproden protected RPE cells from oxidative and inflammatory insults and protected the mouse RPE and retina from RPE atrophy in the face of excess mitochondrial oxidative stress. These results suggest that this drug, which had a reasonable safety profile in clinical trials, may be used to prevent the progression of geographic atrophy in humans.