Affiliation:
1. School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology
of China, Suzhou, China
2. Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of
Science, Suzhou, China
Abstract
Background:
Wet age-related macular degeneration (wAMD) is characterized by the presence
of choroidal neovascularization (CNV). Although there are some clinical drugs targeting vascular
endothelial growth factor (VEGF) and inhibiting CNV, two major side effects limit their application,
including the excessive activity of anti-VEGF and frequent intraocular injections. To explore better
treatment strategies, researchers developed a hypoxic modulator retinal pigment epithelium (RPE)-
specific adeno-associated virus (AAV) vector expressing endostatin to inhibit CNV. However, the
mechanism of endostatin is complex. Instead, soluble fms-like tyrosine kinase-1 (sFlt-1) can inhibit
VEGF-induced angiogenesis through two simple and clear mechanisms, giving rise to sequestration of
VEGF and forming an inactive heterodimer with the membrane-spanning isoforms of the VEGF receptor
Flt-1 and kinase insert domain-containing receptor.
Objective:
In this study, we chose sFlt-1 as a safer substitute to treat wAMD by inhibiting VEGFinduced
angiogenesis.
Methods:
The AAV2/8-Y733F-REG-RPE-sFlt-1 vector was delivered by intravitreal injection to the
eyes of mice. AAV2/8-Y733F vector is a mutant of the AAV2/8 vector, and the REG-RPE promoter is
a hypoxia-regulated RPE-specific promoter. Two animal models were used to evaluate the function of
the vector.
Results:
In the cobalt chloride-induced hypoxia model, the results demonstrated that the AAV2/8-
Y733F-REG-RPE-sFlt-1 vector induced the expression of the sFlt-1 gene in RPE cells through hypoxia.
In the laser-induced CNV model, the results demonstrated that the AAV2/8-Y733F-REG-RPE-sFlt-
1 vector reduced laser-induced CNV.
Conclusions:
Hypoxia regulated, RPE-specific AAV vector-mediated sFlt-1 gene is a hypoxiaregulated
antiangiogenic vector for wAMD.
Funder
National Natural Science Foundation of China
Publisher
Bentham Science Publishers Ltd.
Subject
Genetics (clinical),Drug Discovery,Genetics,Molecular Biology,Molecular Medicine
Cited by
3 articles.
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