Antiangiogenic AAV2 gene therapy with a truncated form of soluble VEGFR-2 reduces the growth of choroidal neovascularization in mice after intravitreal injection
Open accessAbstract
Pathological angiogenesis related to neovascularization in the eye is mediated through vascular endothelial growth factors (VEGFs) and their receptors. Ocular neovascular-related diseases are mainly treated with anti-VEGF agents. In this study we evaluated the efficacy and safety of novel gene therapy using adeno associated virus 2 vector expressing a truncated form of soluble VEGF receptor-2 fused to the Fc-part of human IgG1 (AAV2-sVEGFR-2-Fc) to inhibit ocular neovascularization in laser induced choroidal neovascularization (CNV) in mice. The biological activity of sVEGFR-2-Fc was determined in vitro. It was shown that sVEGFR-2-Fc secreted from ARPE-19 cells was able to bind to VEGF-A165 and reduce VEGF-A165 induced cell growth and survival. A single intravitreal injection (IVT) of AAV2-sVEGFR-2-Fc (1 μl, 4.7 × 1012 vg/ml) one-month prior laser photocoagulation did not cause any changes in the retinal morphology and significantly suppressed fluorescein leakage at 7, 14, 21 and 28 days post-lasering compared to controls. Macrophage infiltration was observed after the injection of both AAV2-sVEGFR-2-Fc and PBS. Our findings indicate that AAV2 mediated gene delivery of the sVEGFR-2-Fc efficiently reduces formation of CNV and could be developed to a therapeutic tool for the treatment of retinal diseases associated with neovascularization.
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IVT injection potentially exposes the entire retina to gene therapy.
“IVT injection potentially exposes the entire retina to gene therapy (Koponen et al., 2021; Puranen et al., 2022), whereas delivery to subretinal space allows direct contact of the vector with photoreceptors and the RPE layers (Irigoyen et al., 2022).”
From AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery (2023) · cites this paper as Puranen et al., 2022
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Koponen, S., Kokki, E., Tamminen, T., & Ylä-Herttuala, S. (2023) · Frontiers in Drug Delivery · doi:10.3389/fddev.2023.1148795 · Cited by 21 · see citing works
Self-citation
- Authors
- Puranen, J., Koponen, S., Nieminen, T., Kanerva, I., Kokki, E., Toivanen, P., Urtti, A., Ylä-Herttuala, S., & Ruponen, M.
- Affiliations
- University of Eastern Finland (FI)
- University of Helsinki (FI)
- Corresponding author
- Puranen, Jooseppi
- Venue
- Experimental Eye Research
- Publisher
- Elsevier BV
- Published
- 2022-11
- Volume
- 224
- Pages
- 109237
- ISSN
- 0014-4835 (ISSN-L)
- OpenAlex
- W4295021522
- Cited by
- 9
- References
- 36
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 3
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Experimental Eye Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- University of Eastern Finland
- Academy of Finland
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- choroidal neovascularization, antiangiogenic gene therapy, AAV2 vector, soluble VEGFR-2, Fc fusion protein, VEGF165, laser photocoagulation, intravitreal injection, ARPE-19 cells, macrophage infiltration, retinal neovascularization, fluorescein leakage
- MeSH terms
- Dependovirus, Animals, Fluoresceins, Genetic Vectors, Humans, Immunoglobulin G, Mice, Inbred C57BL, Genetic Therapy, Choroidal Neovascularization, Angiogenesis Inhibitors, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Mice, Intravitreal Injections
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