Abstract
Purpose :
Cystoid macular edema (CME) is a leading cause of central vision loss in the developed world. Establishing mouse models of cystoid edema is essential for studying CME. We previously reported that late EC-specific inactivation of the Norrin co-receptor Tspan12 (Tspan12 ECKO) bypasses retinal vascular morphogenesis defects but impairs blood-retina barrier (BRB) maintenance. Tspan12 ECKO mice display IgG extravasation, reduced ERG b-wave, and cystoid edema. However, the CME is mild. Here, we report an improved cystoid edema mouse model. The vascular development of conventional Tspan12 KO mice with fully penetrant gene ablation is temporally restored using F4L5.13 Norrin mimetic antibody. At P30, drug treatment is discontinued so that substantial BRB dysfunction occurs, while vascular density is maintained.
Methods :
F4L5.13 was intraperitoneally injected into Tspan12 KO mice from P6 to P27 (every 3 days) and retinal vascular development was quantified. Fluorescein angiography was performed longitudinally from P30 to 6 months to monitor BRB function. ERG was performed longitudinally from P30 to 6 months to examine retinal function. Image-guided OCT system was used to evaluate cystoid edema in adult mice.
Results :
Administration of F4L5.13 from P6 to P27 restored retinal angiogenesis in Tspan12 KO mice. F4L5.13 administration fully restored BRB function in Tspan12 KO mice at P30, but BRB defects gradually appeared after the agonist administration was discontinued. Image-guided OCT showed the development of cystoid lesions and the corresponding vascular leakage areas in Tspan12 KO retinas.
Conclusions :
A novel cystoid edema mouse model is generated by pharmacologically and genetically manipulating Norrin/Frizzled4 signaling. Image-guided OCT system allows for evaluating cystoid edema longitudinally, assessing the effects of CME drug candidates, and performing mechanistic studies.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.