Sustained release of a novel non-fibrate PPARα agonist from microparticles for neuroprotection in murine models of age-related macular degeneration

Prior research has demonstrated the therapeutic potential of peroxisome proliferator-activated receptor α (PPARα) agonist fenofibrate on diabetic retinopathy. In the present study, a novel non-fibrate PPARα agonist, A190, was designed with higher potency and selectivity than fenofibrate in PPARα agonism. A190 was encapsulated in biodegradable microparticles (A190-MP) to ensure sustained drug release, with detection in the retina up to 6 months following a single intravitreal injection. A190-MP alleviated retinal dysfunction as shown by electroretinography in Vldlr^−/− (wet-AMD model) and Abca4^−/−/Rdh8^−/− (dry-AMD model) mice. A190-MP also attenuated the decreases in cone photoreceptor density and outer nuclear layer thickness as demonstrated by optical coherence tomography and histology. Moreover, A190-MP reduced vascular leakage and neovascularization in Vldlr^−/− mice, suggesting an anti-inflammatory and anti-angiogenic effect. A190-MP upregulated expression of PPARα, PGC1α, and TOMM20 in the retina of Vldlr^−/− and Abca4^−/−/Rdh8^−/− mice. A190-MP also improved retinal mitochondrial function as shown by Seahorse analysis using retinal biopsy. In vitro, A190 attenuated oxidative stress and preserved cell viability in a photoreceptor-derived cell line exposed to 4-HNE and improved mitochondrial function, via a PPARα-dependent mechanism. These findings revealed sustained therapeutic effects of A190-MP in wet and dry AMD models, through improving mitochondrial function by activating PPARα.