Targeting pathological corneal neovascularization arising from infection or disease is essential to preserve corneal transparency and avoid vision loss. Aniridia-associated keratopathy (AAK), a rare genetic eye condition caused by PAX6 haploinsufficiency, leads to chronic inflammation, neovascularization, and vision loss, and has limited therapeutic options. Here we evaluated Olisens®, an antisense oligonucleotide targeting insulin receptor substrate-1 (IRS-1), in a Pax6 heterozygous mouse model of AAK. Topical delivery of Olisens for 90 days significantly suppressed pathological blood and lymph vessel ingrowth into the cornea, delaying the disease course. Transcriptomic analysis revealed sustained suppression of immune responses including dendritic cell maturation, macrophage activation, and cell proliferation. Additionally, Olisens enhanced transcripts of epithelial healing factor Lars2 in the cornea and LARS2 protein expression in the peripheral epithelium and normalized peripheral corneal thickness. While vascular regrowth occurred after stopping treatment, immune pathway suppression persisted. Our results indicate targeting IRS-1 using topical Olisens reduces inflammation and neovascularization, thereby delaying AAK progression and suggesting anti-neovascular treatment as a therapeutic strategy for AAK.