Abstract
Purpose :
Intermediate dry age-related macular degeneration (AMD) is characterized by increased oxidative stress and decreased mitochondrial function in the retinal pigment epithelium (RPE), which may be ameliorated by activation of nuclear factor erythroid 2-related factor 2 (NRF2). SCO-116 is a novel NRF2 activator under development for intermediate dry AMD. We evaluated the ability of SCO-116 to protect RPE from oxidative insult in vitro and to protect rat retina in vivo from the prototypical oxidative insult, sodium iodate.
Methods :
Human RPE derived from pluripotent stem cells were plated and matured for 2 weeks prior to insult with A2E for 2 weeks, then challenged with blue light for 3 days. SCO-116 (3 nM) or DMSO was administered at various time points, with cell viability and apoptosis assessed on day 33. For the animal study, geographic atrophy (GA) was induced in 10-week old female Brown Norway rats on study day 4 via bilateral subretinal injection of sodium iodate at 10 μg/eye. On study days 1 and 4 (immediately following GA induction), the animals were administered via bilateral intravitreal (IVT) injection either vehicle or SCO-116 at 3 or 30 μg/eye. On study day 17, optokinetic tracking was used to evaluate visual function by measuring spatial frequency and contrast thresholds, and on study day 21, OCT was used to assess retinal integrity and thickness.
Results :
SCO-116 (3 nM) significantly and completely protected RPE from A2E/blue light damage in vitro at all incubation times studied. In rats, SCO-116 demonstrated improvements in the two visual function measurements compared to control rats. Spatial frequency threshold was 10-12% greater in treated animals, and contrast sensitivity was 8 to 25% greater. Similarly, SCO-116 showed beneficial effects on protecting retinal thickness, with 5 to 17% greater retinal thickness in the treated groups versus controls
Conclusions :
In both RPE in vitro and in the rat subretinal sodium iodate model, an aggressive animal model for GA, SCO-116 demonstrated protection from injury using both functional and structural endpoints. These data support continued investigation of SCO-116 as a potential future development candidate for patients with dry AMD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.