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Nicholas J. Agard, Gu Zhang, John Ridgeway, Danielle M. Dicara, Phillip Y. Chu, Rachana Ohri, Sarah Sanowar, Jean-Michel Vernes, Hannah Chi, Jiameng Zhang, Emily Holz, Maciej Paluch, Guannan He, Yingjia Benson, Jianhuan Zhang, Pamela Chan, Nga Tang, Prachi Javale, Blair Wilson, Kathy Barrett, Rebecca K. Rowntree, Julie Hang, Y. Gloria Meng, Phil Hass, Germaine Fuh, Robert Piskol, Vladimir Bantseev, Kelly M. Loyet, John C. Tran, Cong Wu, Vahan B. Indjeian, Vittal Shivva, Minhong Yan; Direct Tie2 Agonists Stabilize Vasculature for the Treatment of Diabetic Macular Edema. Trans. Vis. Sci. Tech. 2022;11(10):27. doi: https://doi.org/10.1167/tvst.11.10.27.
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Diabetic macular edema (DME) is the leading cause of vision loss and blindness among working-age adults. Although current intravitreal anti-vascular endothelial growth factor (VEGF) therapies improve vision for many patients with DME, approximately half do not achieve the visual acuity required to drive. We therefore sought additional approaches to resolve edema and improve vision for these patients.
We explored direct agonists of Tie2, a receptor known to stabilize vasculature and prevent leakage. We identified a multivalent PEG–Fab conjugate, Tie2.1-hexamer, that oligomerizes Tie2 and drives receptor activation and characterized its activities in vitro and in vivo.
Tie2.1-hexamer normalized and stabilized intercellular junctions of stressed endothelial cell monolayers in vitro, suppressed vascular leak in mice under conditions where anti-VEGF alone was ineffective, and demonstrated extended ocular exposure and robust pharmacodynamic responses in non-human primates.
Tie2.1-hexamer directly activates the Tie2 pathway, reduces vascular leak, and is persistent within the vitreal humor.
Our study presents a promising potential therapeutic for the treatment of DME.
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