This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.

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). Retinal aganirsen concentrations were assessed in rabbits and monkeys after topical delivery (21.5, 43, or 86 g). Clinical significance was further evaluated by determination of IRS-1 expression in monkey and human retinal biopsy specimens. RESULTS. Topical corneal application of aganirsen attenuated neovascular lesion development dose dependently in African green monkeys. The incidence of high-grade CNV lesions (grade IV) decreased from 20.5% in vehicle-treated animals to 1.7% (P Ͻ 0.05) at the 86-g dose. Topical aganirsen inhibited retinal neovascularization after OIR in rats (P Ͻ 0.05); furthermore, a single intravitreal injection of aganirsen reduced OIR as effectively as ranibizumab, and their effects were additive. Significantly, topical applications of aganirsen did not interfere with physiological retinal vessel development in newborn rats. Retinal delivery after topical administration was confirmed, and retinal expression of IRS-1 was demonstrated to be elevated in patients with subretinal neovascularization and AMD. CONCLUSIONS. Topical application of aganirsen offers a safe and effective therapy for both choroidal and retinal neovascularization without preventing its normal vascularization. Together, these findings support the clinical testing of aganirsen for human retinal neovascular diseases. (Invest Ophthalmol Vis Sci.

Angiogenesis is a complex process that is vital to health but is also a driving factor behind a broad range of malignant, ischaemic, inflammatory, infectious and immune disorders. For optimal efficacy and safety, therapies aimed at preventing angiogenic-mediated disorders must differentiate between healthy and pathological angiogenesis or neovascularisation. Aganirsen is an antisense oligonucleotide that inhibits the insulin receptor substrate (IRS)-1 angiogenic pathway by targeting the IRS-1 messenger RNA. To date, studies of aganirsen have focused mainly on ocular disorders because of the ability to assess non-invasively the effect of the drug on neovascularisation and to address the unmet need for effective therapies in these blinding disorders. Aganirsen (GS-101) eye drops inhibit progressive corneal neovascularisation and appear to be well tolerated. The drug may offer an alternative and/or adjunct to intraocular anti-vascular endothelial cell growth factor (VEGF) agents, which are the current reference standards to prevent neovascularisation in retinal diseases. This is because it has a different and potentially complementary mechanism of action and can be administered topically. Antisense oligonucleotides targeting IRS-1 may present a valuable new approach to control pathological angiogenesis in the eye and elsewhere.

No abstract