Retinal ischemia determines treatment effectiveness in mouse model of retinal vein occlusion

Abstract

Purpose : Retinal ischemia is associated with poor vision prognosis in retinal vascular disorders. Anti-VEGF therapies are the current first line of treatment for retinal edema associated with diabetes (DME) or retinal vein occlusion (RVO). However, effectiveness of anti-VEGF therapies in ischemic eyes remains unclear. We investigated the impact of retinal ischemia on treatment response to VEGF inhibition, caspase-9 inhibition, and combination treatment, in a mouse model of RVO.

Methods : RVO was achieved in adult C57/Bl6 mice by tail-vein injection of rose Bengal, followed by laser photocoagulation of retinal veins. In vivo analyses—optical coherence tomography (OCT), fundus imaging, and electroretinograms (ERG)—were conducted with the Micron IV system (Phoenix Research Labs). Mice (n=16-25) received intravitreal injection with 0.4µg VEGF neutralizing antibody (R&D Systems) or PBS 24hr prior to induction of RVO, and received eye-drops containing either 10µg caspase-9 inhibitor (Pen1-XBir3) or Pen1 immediately after RVO and again at 24hr post-RVO.

Results : All treatments improved capillary perfusion 24-48hr post-RVO, reduced hyperreflective foci (HRF), reduced retinal swelling, and improved ERG response. Caspase-9 inhibition and combination treatment were more effective than anti-VEGF at reducing retinal ischemia, and improving retinal morphology and ERG response. Caspase-9 inhibition and combination treatment reduced retinal atrophy; VEGF inhibition had no effect on retinal atrophy. All treatments were equally effective at reducing HRF.

All measures of retinal injury were significantly correlated with degree of retinal ischemia 24hr post-RVO. Caspase-9 inhibition was effective in both ischemic and nonischemic eyes, while VEGF inhibition was effective in low-ischemia eyes. Combination treatment was effective in low-ischemia eyes, and ineffective in eyes with high degree of ischemia.

Conclusions : Retinal ischemia is associated with retinal pathology and functional deficits in the mouse model of RVO. Anti-VEGF and combination treatment are more effective in less ischemic eyes, while caspase-9 inhibition improves pathology in both ischemic and nonischemic eyes.

This is a 2020 ARVO Annual Meeting abstract.