Abstract
Purpose :
Multiple ophthalmic diseases are characterized by decreased mitochondrial function and increased oxidative stress as core pathological features. Nuclear factor erythroid 2-related factor 2 (NRF2) regulates a network of hundreds of antioxidative, anti-inflammatory, and bioenergetic proteins, and NRF2 activation results in increased antioxidative capacity and improved mitochondrial bioenergetics. We evaluated the ability of a novel NRF2 activator, SCO-116, which is under development for macular degeneration and Fuchs’ dystrophy, to induce target protein expression in ocular tissues of rabbits in vivo.
Methods :
SCO-116 was administered via topical ocular administration to male albino (New Zealand White) rabbits. Each rabbit (N=5) was dosed in both eyes once daily for five days with 50 µL of 0.01%, 0.05%, 0.1%, or 0.5% SCO-116 or vehicle (placebo solution). On Day 6, rabbits were sacrificed, and eyes were enucleated and fixed in 10% neutral buffered formalin. Blocks were sectioned at 4 µm and stained with hematoxylin and eosin, with select samples from each globe further processed for immunohistochemistry targeted to NAD(P)H quinone dehydrogenase 1 (NQO1) antigen. Image analysis and quantification were performed using Image-J software.
Results :
SCO-116 significantly and potently induced NQO1 expression in rabbit ocular tissues in a generally dose-dependent manner following once daily dosing for five days. Significant NQO1 induction was observed in the corneal epithelium (up to 2.5-fold over vehicle-treated animals), corneal stroma (1.3-fold), corneal endothelium (3-fold), lens epithelium (2.8-fold), trabecular meshwork (1.7-fold), and retina (1.3-fold). Administration of SCO-116 was well-tolerated.
Conclusions :
As a key regulator of mitochondrial function, activation of NRF2 is an attractive therapeutic approach to multiple ocular diseases ranging from the ocular surface to the retina. Topical ocular administration of SCO-116 efficiently penetrated rabbit eyes to activate NRF2 in multiple ocular tissues, including the retina, with once-daily dosing. These data support the potential therapeutic application of SCO-116 to ocular disease, and support further investigation.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.