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

Invest Ophthalmol Vis Sci. 2012 Mar 9;53(3):1195-203. doi: 10.1167/iovs.11-9064.


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 μg). 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 < 0.05) at the 86-μg dose. Topical aganirsen inhibited retinal neovascularization after OIR in rats (P < 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage*
  • Animals
  • Animals, Newborn
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Fluorescein Angiography
  • Fundus Oculi
  • Gene Expression Regulation / drug effects
  • Humans
  • Insulin Receptor Substrate Proteins / biosynthesis
  • Insulin Receptor Substrate Proteins / genetics*
  • Intravitreal Injections
  • Macular Degeneration / drug therapy*
  • Macular Degeneration / genetics
  • Macular Degeneration / pathology
  • Male
  • Ophthalmic Solutions / administration & dosage
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rabbits
  • Rats
  • Retinal Neovascularization / drug therapy*
  • Retinal Neovascularization / genetics
  • Retinal Neovascularization / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spectrophotometry


  • Angiogenesis Inhibitors
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Ophthalmic Solutions
  • RNA, Messenger