Unity Biotechnology announced preclinical data demonstrating that UBX1325, a novel senolytic small molecule inhibitor of Bcl-xL, improves retinal vasculature and is differentiated from anti-VEGF agents in preclinical models. Researchers show that inhibition of retinal Bcl-xL by UBX1325 selectively promotes apoptosis of diseased senescent cells of the retina, thereby restoring healthy vasculature and improving retinal function—important distinctions from anti-VEGF treatments. The research was presented in a poster presentation, “UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy” during the Association for Research in Vision and Ophthalmology (ARVO) 2021 Annual Meeting.
“The data presented provide important preclinical support for the potential of UBX1325 as a differentiated treatment for prevalent vascular diseases of the eye,” Przemyslaw (Mike) Sapieha, PhD, chief scientific advisor of Unity, said in a company news release. “Retinal vascular diseases, namely diabetic retinopathy and macular edema, are primary causes of blindness in the United States, but current treatments are less than ideal. By targeting the senescent cells that promote inflammation and compromise vascular integrity in the eye, we aim to provide an effective therapeutic option that selectively eliminates diseased and leaky cells within blood vessels while potentially stimulating vascular repair. We are excited that this molecule is now in clinical studies in patients with DME.”
Dr. Sapieha will also participate in a panel discussion at ARVO 2021 focused on neglected pathways in vision loss. The consequences of retinal hypoxia and ischemia and how it triggers apoptosis, cellular senescence and ultimately production of factors that precipitate diabetic retinopathy will be discussed.
Bcl-xL is a molecular target that is highly expressed in diseased blood vessels during retinopathy, which have been shown to engage pathways of cellular senescence. In the study described, the novel senolytic candidate, UBX1325, selectively inhibits Bcl-xL, promoting apoptosis in oxygen induced retinopathy models but not normoxic controls. As demonstrated in models of retinopathy, vascular leakage and retinal function improved following a single injection of UBX1325 as measured by reduced retinal vascular permeability and improvements of retinal neovascularization and avascular area.
Featured in an oral presentation at ARVO 2021, preclinical research of UBX1967, a selective Bcl-xL inhibitor that is molecularly distinct to UBX1325, demonstrated that the inhibition of Bcl-xL suppresses the formation of diseased blood vessels and targets Col1a1-positive endothelial cells that are associated with disease. The data included in the paper, “Inhibition of Bcl-xL with the small molecule UBX1967 targets Col1a1-positive endothelial cells in ischemic retinopathy” further supports the use of senolytic therapies to potentially target pathological vasculature without off-target effects on healthy blood vessels, as seen with anti-VEGF therapeutics.
Unity’s ARVO 2021 poster presentations will be available here after May 5, 2021.