Antiangiogenic Activity of Aganirsen in Nonhuman Primate and Rodent Models of Retinal Neovascular Disease after Topical Administration

Abstract

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.

Topical application of a G-Quartet aptamer targeting nucleolin attenuates choroidal neovascularization in a model of age-related macular degeneration

“…Due to the above unmet needs, the potential for inhibition of CNV through topically delivered drugs has been examined previously (Kiuchi et al, 2008; Sheu et al, 2009; Cloutier et al, 2012; Birke et al, 2013). In our studies, we found an approximate 45% reduction in CNV when 1nmol (8.5μg) of AS1411 was applied once daily one day prior and 7 days post-laser treatment.…”

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

“…2, A and B). It has been suggested that the impaired barrier function of psoriatic lesions (Schittek, 2011) and the amphipathic nature of aganirsen (Cloutier et al, 2012) could facilitate uptake of antisense drugs in general and aganirsen in particular. In agreement, topical applications of aganirsen decreased psoriatic plaque area in both groups of patients (0.86 and 1.72 mg/g) compared with placebo.…”

“…Nonetheless, because both angiogenesis and inflammation are involved in the development of psoriasis, we speculated that aganirsen (GS-101) could be efficient in psoriatic patients. Aganirsen is an antisense oligonucleotide that inhibits the expression of insulin receptor substrate-1 (IRS-1) and has antiangiogenic activities, including inhibition of both VEGF and IL-1b expression (Andrieu-Soler et al, 2005;Al-Mahmood et al, 2009;Cloutier et al, 2012). In this study, we show that, by inhibiting IRS-1 expression in the cytoplasmic compartment, aganirsen impaired 14-3-3b-tristetraprolin protein (TTP) complex formation, leading to the inhibition of the expression of several cytokines with AU-rich mRNA, including , and TNFa.…”

Antilymphangiogenic therapy to promote transplant survival and to reduce cancer metastasis: What can we learn from the eye?

“…Aganirsen will be the first therapeutic that will be approved for the topical treatment of corneal neovascularization. Since Aganirsen eye drops in primate models also reached sufficient levels at the retina and choroidea, Aganirsen also holds great promise for novel topical treatment options against AMD and retinal vascular diseases [92].…”