Therapeutic targeting of cellular senescence in diabetic macular edema: results from preclinical and phase 1 trials
Compromised vascular endothelial barrier function is a hallmark of diabetic complications, such as sight-threatening diabetic macular edema (DME). Current standards of treatment for DME manage some aspects of the disease, but require frequent intravitreal administrations and are poorly effective in many patients. Here we provide evidence that a high burden of senescent cells in the retina triggers the cardinal features of DME pathology and conduct a first test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia induced cellular senescence in subsets of vascular endothelial cells, displaying disrupted transendothelial junctions, associated with impaired barrier function and leading to microinflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 safety study with escalating doses of UBX1325 (foselutoclax), a small molecule senolytic inhibitor of BCL-xL, in patients with advanced DME, for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of evaluating the safety and tolerability of UBX1325 was met. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor could offer a durable, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov Identifier: NCT04537884.
