Downregulation of IRS-1 Expression Causes Inhibition of Corneal Angiogenesis

Abstract

Subconjunctival injections of IRS-1 antisense ODN significantly inhibit rat corneal neovascularization. This effect may be mediated by a downregulation of IL-1beta. IRS-1 proteins may be interesting targets for the regulation of angiogenesis mediated by insulin, hypoxia, or inflammation.

Tolerability and safety of GS‐101 eye drops, an antisense oligonucleotide to insulin receptor substrate‐1: a ‘first in man’ Phase I investigation

“…Partial IRS-1 inhibition by GS-101 induced a significant inhibition of both VEGF-A and interleukin-1β transcription in cultured human endothelial cells associated with complete inhibition of capillary-like tube formation [17], an in vitro model of angiogenesis. Accordingly, topical administration of GS-101 in the injury-induced corneal neovascularization rat model inhibited in vivo angiogenesis [17, 18]. The results of this ‘first-in-man’ open-label Phase I tolerability study reported here demonstrate that GS-101 is well tolerated in healthy human subjects.…”

“…IRS-1 involvement in angiogenesis has been demonstrated in vitro and in animal experiments, and the ability of GS-101 to inhibit IRS-1 has been validated [17, 18]. Previous in vitro investigations have shown that GS-101 inhibits IRS-1 expression in human endothelial cells placed under different angiogenic stimuli [17].…”

“…GS-101 inhibits the expression of IRS-1 [17]. This inhibition of IRS-1 results in the prevention of neovascular growth and has been reported to prevent the angiogenic process in preclinical in vivo and in vitro experiments [17, 18]. Specifically, the neovascularization-related orphan indications of corneal graft rejection, retinopathy of pre-maturity and neovascular glaucoma are being targeted as initial clinical applications of GS-101.…”

Citicoline induces angiogenesis improving survival of vascular/human brain microvessel endothelial cells through pathways involving ERK1/2 and insulin receptor substrate-1

“…Only recently, IRS-1 over-expression was attributed to increased angiogenesis in human EC in association with increased Akt and VEGF-A expression [12], whilst in vivo , antisense IRS-1 sequences delivered by sub-conjunctival injection inhibited rat corneal neovascularisation [21], and when delivered by means of eye-drops (GS-101) were found to be tolerable in a phase-1 clinical trial and may be sufficient to prevent neovascularisation in disease such as retinopathy and neovascular glaucoma [22]. Therefore, IRS-1 represents a potent modulator of pro-angiogenic signalling cascades in vascular EC and as such, since we have shown both in vitro , and in the rat model of temporary MCAO that citicoline induces phosphorylation of IRS-1 and concomitant EC activation and increased vascularisation, this could be a key novel mechanism of action of citicoline.…”

Role of Endogenous Regulators of Hem- And Lymphangiogenesis in Corneal Transplantation

“…Binding of VEGF-A and VEGF-B to VEGFR-1 and VEGFR-2 induces hemangiogenesis [6][7][8]. In addition, the cytokines platelet-derived growth factor (PDGF) [9], fibroblast growth factor-2 (FGF-2), placental growth factor (PIGF), hepatocyte growth factor (HGF) [10] and the adapter protein insulin receptor substrate-1 (IRS-1) [11] have also been found to induce hemangiogenesis.…”