Antiangiogenic activity of aganirsen in nonhuman primate and rodent models of retinal neovascular disease after topical administration.
OBJECTIVE
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.
Department of Pediatrics, Ophthalmology, Pharmacology, Hôpital Ste-Justine, Université de Montréal, Montreal, Quebec, Canada.
Frank
F
Cloutier
Matthew
M
Lawrence
Robin
R
Goody
Stéphanie
S
Lamoureux
Salman
S
Al-Mahmood
Sylvie
S
Colin
Antoine
A
Ferry
Jean-Pascal
JP
Conduzorgues
Amel
A
Hadri
Claus
C
Cursiefen
Patricia
P
Udaondo
Eric
E
Viaud
Eric
E
Thorin
Sylvain
S
Chemtob
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis / Q000235:genetics*; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D009883:Ophthalmic Solutions / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D051381:Rats; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013053:Spectrophotometry
D020533:Angiogenesis Inhibitors; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009883:Ophthalmic Solutions; D012333:RNA, Messenger