PROTAC based targeted degradation of LRG1 for mitigating corneal neovascularization

Abstract

Leucine-rich alpha-2-glycoprotein 1 (LRG1), a secretory glycoprotein associated with angiogenesis, inflammation, fibrosis, and other pivotal pathophysiological processes, is significantly upregulated in corneal neovascularization (CNV), where it drives neovascularization via the TGF-β-Smad signaling pathway, making it a potential therapeutic target for CNV. This study employs proteolysis-targeting chimera (PROTAC) technology, utilizing our newly developed PROTAC agent, ^ETTAC-2, to selectively degrade LRG1 in a mouse model of alkali burn-induced CNV. The cellular study revealed that ^ETTAC-2 effectively degraded LRG1 in a time- and dose-dependent manner, with a half-maximal degradation concentration (DC50) of 13.52 μM. In vivo findings confirmed that ^ETTAC-2 significantly reduced LRG1 levels in corneal neovascular tissues and inhibited the release of angiogenic factors by suppressing the TGF-β-Smad1/5/9 pathway, thus attenuating CNV progression. To enhance corneal drug delivery, ^ETTAC-2 was encapsulated in liposomes to form Lipo@^ETTAC-2, which enhanced drug retention on the corneal surface, resulting in superior therapeutic outcomes in CNV models. This study underscores the pivotal role of LRG1 in CNV and positions Lipo@^ETTAC-2 as a promising candidate for CNV therapy.