Development of Two Novel AMD Models for Evaluation of RPE Protection by the Novel Antioxidant D-DHA

PROJECT SUMMARY Geographic atrophy (GA) is the advanced form of dry age-related macular degeneration. Recently, anti-complement drugs have shown moderate efficacy in slowing disease progression. The long-term goals of the proposed studies are to develop two new mouse models of GA based on RPE oxidative stress for testing potential novel therapeutics. We will test one such therapeutic, oral deuterated docosahexanoic acid (D-DHA), which has shown considerable promise in an acute model of photoreceptor oxidative stress caused by intravitreal iron injection. Oxidation of DHA has been implicated in AMD pathogenesis by Joe Hollyfield's lab. Now it is important to determine whether this oxidation-resistant form of DHA can protect the RPE from GA formation and expansion. The approach is to study RPE-specific glutathione peroxidase 4 knockout mice, as well as mice given a low dose of sodium iodate, which causes an expanding patch of GA in the superior retina. The degeneration will be characterized using in vivo imaging (cSLO and OCT), ERG, and, after euthanasia, mass spectrometry, histology, IHC, and qPCR. The impact will be to generate new GA models and to assess the potential of a promising new oral drug for prevention or treatment of AMD.