Therapeutic senolysis improves vascular function during diabetic retinopathy

Abstract

Purpose : Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). While current standards of care manage symptoms, they require frequent intravitreal administration and are not effective in large subsets of patients.

Methods : In vitro studies were performed using human retinal microvascular endothelial cells subjected to chronic exposure to high glucose (25mM D-Glucose). L-Glucose was used as osmotic control. In vivo, we used a mouse model of streptozotocin-induced diabetes (10 weeks of diabetes). UBX1967, a senolytic small molecule inhibitor of the anti-apoptotic protein BCL-xL, was administered intravitreally. qPCR, single-cell (sc) and bulk RNA-Seq were performed for transcriptomic analyses. Protein expression was studied by Western blot or tissue immunolabelling. All animal studies complied with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and were approved by institutional ethical committees.

Results : Sustained hyperglycemia triggered DNA damage in vascular endothelial cells culminating in cellular senescence and micro-inflammation linked to the senescence-associated secretory phenotype (SASP). Senescent endothelial cells had perturbed transendothelial-cadherin junctions, exposing vulnerabilities for barrier function. Intravitreal treatment with UBX1967 prevented diabetes-induced retinal vascular leakage, reduced retinal inflammation, and preserved retinal function in mice.

Conclusions : Therapeutic clearance of senescent cells from the diabetic retina with UBX1967 may provide a novel, non-VEGF-based approach to treat diabetes-related retinal complications.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.