March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Topical Administration Of An Antisense Oligonucleotide Targeting Insulin Receptor Substrate-1 Inhibits Choroidal Neovascularization In A Nonhuman Primate Laser-induced Model
Author Affiliations & Notes
  • Matthew Lawrence
    Research, RxGen, Hamden, Connecticut
  • Robin Goody
    Research, RxGen, Hamden, Connecticut
  • Eric Thorin
    Research, Gene Signal, Boulogne, France
  • Eric Viaud
    Research, Gene Signal, Boulogne, France
  • Footnotes
    Commercial Relationships  Matthew Lawrence, RxGen (E); Robin Goody, RxGen (E); Eric Thorin, Gene Signal (P); Eric Viaud, Gene Signal (I, E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2269. doi:
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      Matthew Lawrence, Robin Goody, Eric Thorin, Eric Viaud; Topical Administration Of An Antisense Oligonucleotide Targeting Insulin Receptor Substrate-1 Inhibits Choroidal Neovascularization In A Nonhuman Primate Laser-induced Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2269.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Aganirsen, an antisense oligonucleotide which inhibits the expression of insulin receptor substrate-1, has been shown to promote regression of pathological corneal neovascularization in patients. In this study, we aimed to demonstrate the anti-angiogenic activity of Aganirsen in a nonhuman primate model of choroidal neovascularization (CNV) following topical administration.

Methods: : A previously validated nonhuman primate model of laser-induced CNV was used to evaluate anti-angiogenic activity of Aganirsen. Eye drops of Aganirsen or vehicle were applied daily to 26 African green monkeys for 16 days, beginning two days prior and continuing for 14 days post-laser photocoagulation. Six laser spots were concentrically placed on each eye approximately 1.5 disc diameters from the fovea. Fluorescein angiography was conducted 4 weeks after laser photocoagulation to evaluate fluorescein leakage and spot fluorescein intensity. Optical coherence tomography (OCT) was performed to evaluate neovascular complex formation. Neovascular leakage was evaluated by examiners masked to treatment employing a well-validated grading system, whereby grade III and IV lesions denote clinically relevant CNV, with additional quantification of fluorescein signal intensity and lesion area.

Results: : Topical corneal application of Aganirsen attenuated neovascular lesion development in a dose-dependent manner in African green monkeys: incidence of high grade CNV lesions (grade IV) decreased from 20.5% in vehicle-treated animals to 11.1 (p=0.09), 8.3 (p=0.08) and 1.7% (p<0.05) at daily doses of 21.5, 43 and 86 µg, respectively. Grade III lesion incidence decreased dose-dependently and was paralleled by a dose-dependent increase in grade II lesions. Grade I lesions, indicating minimal CNV formation, were only seen in animals treated with the highest dose. Furthermore, fluorescein signal intensity was significantly lower only in lesions from animals receiving high dose Aganirsen than those receiving vehicle (p<0.05). The size of CNV complexes was also significantly lower in eyes receiving high dose and low dose Aganirsen (p< 0.0001) compared with vehicle-treated eyes.

Conclusions: : Topical application of Aganirsen offers a promising therapy for choroidal neovascularization, inhibiting neovascular growth and leakage. This work strongly supports clinical testing of Aganirsen for human retinal neovascular diseases.

Keywords: age-related macular degeneration • choroid: neovascularization • laser 
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