miR-15a-5p outperforms anti-VEGF drug in ocular neovascularization by providing dual anti-angiogenic and neuroprotective effects.

BACKGROUND: Pathological ocular neovascularization is a major driver of vision-threatening retinal diseases. This study aimed to investigate the role and therapeutic potential of miR-15a-5p in ocular neovascular disorders. METHODS: miR-15a-5p expression levels were assessed in intraocular fluids from patients with ocular neovascular diseases. Functional assays were performed in retinal endothelial cells under pathological conditions to evaluate proliferation and endothelial-to-mesenchymal transition. In vivo, miR-15a-5p was delivered via intravitreal injection in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) mouse models. Therapeutic effects on pathological neovascularization were analyzed and compared with anti-VEGF treatment, including assessments of retinal structural integrity, retinal function, gliosis, and fibrotic changes. miR-15a-5p-knockout mice were used to examine retinal vascular developmental abnormalities and enhanced neovascular responses following miR-15a-5p deficiency. Safety evaluations of systemic and ocular administration were performed in both healthy and neovascularized mice. Mechanistic studies investigated whether miR-15a-5p directly targeted VEGF and Smad2. RESULTS: miR-15a-5p was significantly upregulated in intraocular fluids from patients with ocular neovascular diseases. Overexpression of miR-15a-5p inhibited retinal endothelial cell proliferation and endothelial-to-mesenchymal transition in vitro. In OIR and CNV models, miR-15a-5p treatment reduced retinal neovascularization, decreased reactive gliosis, and maintained retinal thickness and electrophysiological function. In miR-15a-5p-knockout mice, loss of miR-15a-5p impaired normal retinal vascular development. Mechanistically, miR-15a-5p directly targeted VEGF and Smad2, modulating angiogenic and fibrotic pathways. Compared with anti-VEGF therapy, miR-15a-5p demonstrated stronger anti-fibrotic and neuroprotective effects without affecting postnatal development or systemic metabolism. No ocular or systemic toxicity was observed at therapeutic doses. CONCLUSIONS: miR-15a-5p regulates angiogenesis and fibrosis by targeting VEGF and Smad2. These findings suggest that miR-15a-5p is a promising therapeutic candidate for the treatment of ocular neovascular diseases.