Beiying Qiu1, Alison Tan1, Amutha Barathi Veluchamy2,3,4, Yong Li1,2, Hannah Murray1, Wei Cheng1, Chenghao Liu5, Joanna Marie Busoy2, Qi-Yin Chen6, Srivani Sistla1, Walter Hunziker1,7, Chui Ming Gemmy Cheung2,3, Tien Yin Wong2,3, Wanjin Hong1, Hendrik Luesch5,6,8, Xiaomeng Wang1,2,5,9. 1. Institute of Molecular and Cell Biology, Agency for Science Technology & Research, Singapore. 2. Singapore Eye Research Institute, Singapore National Eye Center, Singapore. 3. Duke-NUS Medical School, National University of Singapore, Singapore. 4. Department of Ophthalmology, Yong Loo Lin School of Medicine, Singapore. 5. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore. 6. Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, Florida, United States. 7. Department of Physiology, National University Singapore, Singapore. 8. Oceanyx Pharmaceuticals, Inc., Woburn, Massachusetts, United States. 9. Institute of Ophthalmology, University College London, United Kingdom.
Abstract
Purpose: Abnormal blood vessel formation is a defining feature of many blinding eye diseases. Targeting abnormal angiogenesis by inhibiting VEGF has revolutionized the treatment of many ocular angiogenic diseases over the last decade. However, a substantial number of patients are refractory to anti-VEGF treatment or may develop resistance over time. The objective of this study was to determine the efficacy and the mechanism of action of Apratoxin S4 in ocular angiogenesis. Methods: Retinal vascular cell proliferation, migration, and the ability to form tube-like structure were studied in vitro. Ex vivo aortic ring, choroid, and metatarsal assays were used to study Apratoxin S4's impact on vessel outgrowth in a multicellular environment. Apratoxin S4 was also tested in mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), and in a rabbit model of persistent retinal neovascularization (PRNV). Western blot and ELISA were used to determine the expression of key angiogenic regulators after Apratoxin S4 treatment. Results: Apratoxin S4 strongly inhibits retinal vascular cell activation by suppressing multiple angiogenic pathways. VEGF-activated vascular cells and angiogenic vessels are more susceptible to Apratoxin S4 treatment than quiescent vascular cells and vessels. Both intraperitoneal and intravitreal delivery of Apratoxin S4 are able to impede ocular neovascularization in vivo. Apratoxin S4 specifically attenuates pathological ocular angiogenesis and exhibits a combinatorial inhibitory effect with standard-of-care VEGF inhibitor drug (aflibercept). Conclusions: Apratoxin S4 is a potent antiangiogenic drug that inhibits the activation of retinal endothelial cells and pericytes through mediating multiple angiogenic pathways.
Purpose: Abnormal blood vessel formation is a defining feature of many blinding eye diseases. Targeting abnormal angiogenesis by inhibiting VEGF has revolutionized the treatment of many ocular angiogenic diseases over the last decade. However, a substantial number of patients are refractory to anti-VEGF treatment or may develop resistance over time. The objective of this study was to determine the efficacy and the mechanism of action of Apratoxin S4 in ocular angiogenesis. Methods: Retinal vascular cell proliferation, migration, and the ability to form tube-like structure were studied in vitro. Ex vivo aortic ring, choroid, and metatarsal assays were used to study Apratoxin S4's impact on vessel outgrowth in a multicellular environment. Apratoxin S4 was also tested in mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), and in a rabbit model of persistent retinal neovascularization (PRNV). Western blot and ELISA were used to determine the expression of key angiogenic regulators after Apratoxin S4 treatment. Results:Apratoxin S4 strongly inhibits retinal vascular cell activation by suppressing multiple angiogenic pathways. VEGF-activated vascular cells and angiogenic vessels are more susceptible to Apratoxin S4 treatment than quiescent vascular cells and vessels. Both intraperitoneal and intravitreal delivery of Apratoxin S4 are able to impede ocular neovascularization in vivo. Apratoxin S4 specifically attenuates pathological ocular angiogenesis and exhibits a combinatorial inhibitory effect with standard-of-care VEGF inhibitor drug (aflibercept). Conclusions: Apratoxin S4 is a potent antiangiogenic drug that inhibits the activation of retinal endothelial cells and pericytes through mediating multiple angiogenic pathways.
Authors: Marie O Pohl; Laura Martin-Sancho; Ranjala Ratnayake; Kris M White; Laura Riva; Qi-Yin Chen; Gauthier Lieber; Idoia Busnadiego; Xin Yin; Samuel Lin; Yuan Pu; Lars Pache; Romel Rosales; Marion Déjosez; Yiren Qin; Paul D De Jesus; Anne Beall; Sunnie Yoh; Benjamin G Hale; Thomas P Zwaka; Naoko Matsunaga; Adolfo García-Sastre; Silke Stertz; Sumit K Chanda; Hendrik Luesch Journal: ACS Infect Dis Date: 2022-06-29 Impact factor: 5.578
Authors: Weijing Cai; Ranjala Ratnayake; Mengxiong Wang; Qi-Yin Chen; Kevin P Raisch; Long H Dang; Brian K Law; Hendrik Luesch Journal: Curr Res Pharmacol Drug Discov Date: 2021-09-08