GYT-088 Restores Endothelial Function and Prevents Retinal Vascular Pathology in Non-proliferative and Proliferative Diabetic Retinopathies

Export Diabetic retinopathy remains a leading cause of vision impairment worldwide, with early stages characterized by endothelial dysfunction and later stages marked by pathological neovascularization. Although intravitreal antivascular endothelial growth factor (VEGF) therapies are effective in advanced stages, they show limited efficacy in correcting early vascular dysfunction and macular edema. This study explores the therapeutic potential of GYT-088, a metabolite derived from medicinal fungi, in restoring retinal vascular function at noncytotoxic concentrations. In a type 2 diabetic rhesus monkey model that closely resembles human disease, systemic GYT-088 (6 mg/kg) improved macular edema in two of three animals without altering glucose metabolism. Retinal vessel tortuosity and perivascular changes were also reduced. In a murine model of laser-induced neovascularization, intravitreal GYT-088 suppressed pathological angiogenesis in a dose- and time-dependent manner, showing efficacy comparable to the anti-VEGF agent Eylea. Optical coherence tomography imaging further confirmed preservation of retinal layer structure and reduction of hyperreflective foci. In vitro studies revealed that GYT-088 upregulated endothelial nitric oxide (NO) synthase and claudin-5, while suppressing caveolin-1 (CAV1) expression – leading to increase NO production and reinforced endothelial barrier function. Mechanistic experiments confirmed CAV1 as a negative regulator of GYT-088-mediated vascular protection. Together, these findings support GYT-088 as a promising therapeutic candidate for improving nonproliferative and proliferative diabetic retinopathies.