A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization
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ORIGINAL PAPER
A drug‑tunable Flt23k gene therapy for controlled intervention in retinal neovascularization Jinying Chen1,2 · Fan‑Li Lin2,3 · Jacqueline Y. K. Leung4 · Leilei Tu1 · Jiang‑Hui Wang5 · Yu‑Fan Chuang2,4 · Fan Li2,6 · Hsin‑Hui Shen7,8 · Gregory J. Dusting5,9 · Vickie H. Y. Wong10 · Leszek Lisowski11,12,13 · Alex W. Hewitt2,5,9 · Bang V. Bui10 · Jingxiang Zhong1 · Guei‑Sheung Liu1,2,9 Received: 3 February 2020 / Accepted: 4 September 2020 © Springer Nature B.V. 2020
Abstract Gene therapies that chronically suppress vascular endothelial growth factor (VEGF) represent a new approach for managing retinal vascular leakage and neovascularization. However, constitutive suppression of VEGF in the eye may have deleterious side effects. Here, we developed a novel strategy to introduce Flt23k, a decoy receptor that binds intracellular VEGF, fused to the destabilizing domain (DD) of Escherichia coli dihydrofolate reductase (DHFR) into the retina. The expressed DHFR(DD)-Flt23k fusion protein is degraded unless “switched on” by administering a stabilizer; in this case, the antibiotic trimethoprim (TMP). Cells transfected with the DHFR(DD)-Flt23k construct expressed the fusion protein at levels correlated with the TMP dose. Stabilization of the DHFR(DD)-Flt23k fusion protein by TMP was able to inhibit intracellular VEGF in hypoxic cells. Intravitreal injection of self-complementary adeno-associated viral vector (scAAV)-DHFR(DD)-Flt23k and subsequent administration of TMP resulted in tunable suppression of ischemia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy (OIR). Hence, our study suggests a promising novel approach for the treatment of retinal neovascularization. Jingxiang Zhong and Guei-Sheung Liu contributed equally to this work as senior author. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09745-7) contains supplementary material, which is available to authorized users. * Guei‑Sheung Liu [email protected] 1
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Department of Biochemistry and Molecular Biology, School of Biomedical Science, Monash University, Clayton, VIC, Australia
Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia
Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
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Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
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Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC, Australia
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Translational Vectorology Group, Children’s Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, TAS, Australia
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Centre for Eye Research Australia, Ro
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