Abstract
Purpose: :
Ischemic retinal vein occlusion (RVO) is a common retinal vascular disorder and carries a high risk of visual morbidity with few therapeutic options. We evaluated whether dual inhibition of VEGFR and down-stream Src family tyrosine kinases using small molecules is a potential therapeutic intervention for ischemic retinal vascular disorders.
Methods: :
We examined two distinct chemical classes of dual VEGFR/Src kinase inhibitors (represented by compounds TG100801 and TG100948) in a rat model of RVO for their ability to impact retinal edema. Ischemic retinal vein occlusion was induced in rat retina by thrombosis of a single retinal vein using argon laser photocoagulation following injection of a photo-sensitizer dye. Edema was quantified either using scanning optical fluorophotometry, measuring fluorescein leakage in to the retina, or by optical coherence tomography (OCT), measuring retinal thickness.
Results: :
Following topical administration, both the compounds achieved substantial levels in the retina and intraocular tissues with little to no systemic exposure. At 48 hrs post-vein occlusion, both TG100801 and TG100948 successfully reduced edema compared to vehicle (by 47% with 0.3% TG100801, P= 0.002, and by 38% with 0.03% TG100948, P= 0.039). OCT scans also showed reduced retinal thickening as well as resolution of pockets of bullous edema.
Conclusions: :
As VEGF plays a key role in the edema and neovascularization which develop in the ischemic retina, we propose that multi-targeted inhibitors of the VEGF signaling cascade represent promising therapies for these vascular disorders. Moreover, as current forms of therapy require invasive delivery techniques (intravitreal injections), compounds such as TG100801 and TG100948, which can be topically delivered, offer additional therapeutic advantages.
Keywords: ischemia • retinal neovascularization • edema