Endothelial CLK2 as a therapeutic target for acute radiation syndrome
Posey, R. R.; Ozkan, A.; Man, Y.; Feitor, J. F.; Jiang, A.; Ji, J.; LoGrande, N. T.; Kyprianou, C.; Howley, A. M.; Budnik, B.; Lee, J. D.; Chou, D. B.; Ingber, D. E.
Show abstract
Damage to the vascular endothelium is a major contributor to acute radiation injury in multiple organs that underlies acute radiation syndrome (ARS), yet there are no FDA-approved radiation countermeasures targeting endothelial cells. Use of kinome-scale CRISPR screens performed in cultured human vascular endothelial cells isolated from different organs identified CLK2 as a potential radioprotective target. Pharmacological inhibition of CLK2 using TG003 and Cirtuvivint protected these endothelial cells against radiation injury and reversed its effects across the transcriptome and phospho-proteome. Human Organ Chip models of human intestine and lung that contain organ-specific epithelium and microvascular endothelium faithfully replicated clinical features of ARS when exposed to radiation, which were prevented when treated with CLK2 inhibitors. Thus, CLK2 inhibitors may represent a new class of radiation countermeasure drugs that can protect multiple organs against radiation-induced toxicities in patients with ARS.
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