Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study.

Objective: Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation.

Design: Multicenter, double-masked, randomized, placebo-controlled phase III study.

The antiangiogenic insulin receptor substrate-1 antisense oligonucleotide aganirsen impairs AU-rich mRNA stability by reducing 14-3-3β-tristetraprolin protein complex, reducing inflammation and psoriatic lesion size in patients.

Increased inflammation and aberrant angiogenesis underlie psoriasis. Here, we report that the inhibition of insulin receptor substrate-1 (IRS-1) expression with aganirsen resulted in a dose-dependent reduction (P < 0.0001) in IRS-1 protein in the cytoplasm, while IRS-1 protein remained quantitatively unchanged in the perinuclear environment.

Antiangiogenic activity of aganirsen in nonhuman primate and rodent models of retinal neovascular disease after topical administration.

Purpose: Aganirsen, an antisense oligonucleotide inhibiting insulin receptor substrate (IRS)-1 expression, has been shown to promote the regression of pathologic corneal neovascularization in patients. In this study, the authors aimed to demonstrate the antiangiogenic activity of aganirsen in animal models of retinal neovascularization.

Methods: Eyedrops of aganirsen were applied daily in nonhuman primates after laser-induced choroidal neovascularization (CNV; model of wet age-related macular degeneration [AMD]) and in newborn rats after oxygen-induced retinopathy (OIR; model of ischemic retinopathy).

Potent in vivo antiangiogenic effects of GS-101 (5'-TATCCGGAGGGCTCGCCATGCTGCT-3'), an antisense oligonucleotide preventing the expression of insulin receptor substrate-1.

Angiogenesis is a complex phenomenon regulated by both pro- and antiangiogenic factors such as the vascular endothelial growth factor (VEGF), and inflammation may be involved in the process. Although antagonizing VEGF has been proposed as a therapeutic approach to limit corneal angiogenesis, alternative targets are needed. In this study, we demonstrate that, under proangiogenic experimental conditions, human endothelial cells (hECs) express more insulin receptor substrate (IRS)-1 proteins relative to quiescent cells.