Journal article

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization

Jinying Chen, Fan-Li Lin, Jacqueline YK Leung, Leilei Tu, Jiang-Hui Wang, Yu-Fan Chuang, Fan Li, Hsin-Hui Shen, Gregory J Dusting, Vickie HY Wong, Leszek Lisowski, Alex W Hewitt, Bang V Bui, Jingxiang Zhong, Guei-Sheung Liu

Angiogenesis | SPRINGER | Published : 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 fusio..

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Grants

Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by National Natural Science Foundation of China


Awarded by NHMRC Practitioner Fellowship


Awarded by Department of Science and Higher Education of Ministry of National Defense, Republic of Poland ("Kociuszko")


Awarded by National Science Centre, Republic of Poland


Funding Acknowledgements

The authors thank UTAS CFF animal technicians, Karen Shiels, Keri Smith, Heather Howard, Lisa Harding and Danielle Eastley, for their assistance with rat chamber operation. This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC; 1061912, 1185600, 1108311 and 1161583), the Ophthalmic Research Institute of Australia, the National Natural Science Foundation of China (8197030485) and the Rebecca L Cooper Medical Research Foundation. A.W.H. received an NHMRC Practitioner Fellowship (1103329). L.L. was supported by the Department of Science and Higher Education of Ministry of National Defense, Republic of Poland ("Kociuszko" k/10/8047/DNiSW/T-WIHE/3) and the National Science Centre, Republic of Poland (UMO-2017/25/B/NZ1/02790). The Centre for Eye Research Australia receives Operational Infrastructure Support from the Victorian Government.