Effects of OC-10X, a Novel Inhibitor of Tubulin, in a Rat Choroidal Neovascularization Model

Abstract

Purpose: : Exudative age-related macular degeneration (AMD) due to choroidal neovascularization (CNV) is a leading cause of blindness in developed countries. Current, therapeutic emphasis for treatment of AMD targets VEGF or VEGF receptors to block CNV formation. Pharmacokinetic studies showed penetration of topically applied OC-10X into the retina and excretion in the urine with subclinical levels in plasma and other tissues. We examined the ability of OC-10X to inhibit tubulin in antiangiogenic and angiolytic rat CNV models versus untreated control groups.

Methods: : Male Brown Norway rats were anesthetized and then 8 photocoagulation spots applied to right eye around the optic disk using an argon laser. Tocrisolve^TM was used as vehicle for 1% OC-10X. Control group rats (n=6) received no treatment versus anti-angiogenesis model (n=11) which started receiving treatment before laser and angiolytic model (n=11) which received treatment starting 2 wk after laser. Two wk is adequate for angiogenesis to develop in rat CNV models. Rats were monitored weekly after laser with fluorescein funduscopy for 6 wk. Ocular toxicity was studied for upto 8 wk with topical TID application. Eyes were examined with slit lamp examination for signs of toxicity using a modified McDonald-Shadduck System: Slit Lamp Scale for Ocular Irritation and also by multifocal and full field electroretinogram (ERGs). Rats were then euthanized and eyes removed for histologic analysis after IV injection of fluorescein-dextran injection. Cross sections of retina and cornea were examined after H&E staining for light microscopy.

Results: : In the anti-angiogenesis model, rats were treated with OC-10X for 4 days prior to laser induction and after for 6 wk. In the angiolytic model, treatment started 2 wk after laser induction for a total of 6 wk post laser. Topical treatment decreased CNV up to 45% in the anti-angiogenesis model and by 35% in the angiolytic model compared to the untreated control group. No toxic effects were noted after topical application of OC-10X as determined by slit lamp and light microscopy. Likewise, OC-10X had no deleterious effect on retinal function as quantified by ERG.

Conclusions: : Topical treatment with OC-10X reduces laser-induced CNV in both antiangiogenic and angiolytic models. The compound shows no ocular toxicity in these rat models, suggesting that topical application of OC-10X consititutes a new approach to inhibit neovascular pathologies in AMD.

Keywords: age-related macular degeneration