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Updated: Jan 28, 2026
A Mouse Model for Laser-induced Choroidal Neovascularization
Published on: December 27, 2015
Suppression of Choroidal Neovascularization by AAV-Based Dual-Acting Antiangiogenic Gene Therapy
Anne Louise Askou1, Sidsel Alsing1, Josephine N E Benckendorff1
1Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
Abstract:
Vascular endothelial growth factor A (VEGFA) is involved in the pathogenesis of vasoproliferative retinal diseases, such as exudative age-related macular degeneration (AMD). The objective of this study was to investigate whether dual-acting therapy based on the simultaneous expression of anti-VEGFA microRNAs (miRNAs) and the secreted, antiangiogenic protein pigment endothelial-derived factor (PEDF) delivered by adeno-associated virus (AAV) vectors provides improved protection against choroidal neovascularization (CNV). To investigate this, a multigenic AAV vector allowing retina pigment epithelium (RPE)-specific expression of anti-VEGFA miRNAs and PEDF was engineered. Robust expression of PEDF, driven by the RPE-specific vitelliform macular dystrophy 2 promoter, was observed in human cells and in mouse retina. A significant reduction in CNV was observed in a laser-induced CNV mouse model 57 days post-injection of the AAV5 particles conveying either anti-VEGFA miRNA and PEDF dual therapy or anti-VEGFA miRNA monotherapy. Overall, CNV reduction was most prominent in animals receiving dual-acting therapy. In both cases, the reduction in CNV was accompanied by a significant attenuation of VEGFA. In conclusion, the presented data reveal that gene therapy targeting VEGFA via multigenic AAV vectors displays combined efficacy, suggesting that dual-acting therapy is an important tool in future eye gene therapy for the treatment of neovascular ocular diseases, including AMD.
Insights
Dual gene therapy using adeno-associated virus (AAV) vectors expressing anti-VEGFA microRNAs and pigment endothelial-derived factor (PEDF) effectively reduced choroidal neovascularization (CNV) in a mouse model, offering potential for treating neovascular eye diseases like AMD.
Area of Science:
- Ophthalmology
- Gene Therapy
- Molecular Biology
Background:
- Vascular endothelial growth factor A (VEGFA) drives vasoproliferative retinal diseases, including exudative age-related macular degeneration (AMD).
- Choroidal neovascularization (CNV) is a key pathological feature in AMD, leading to vision loss.
Purpose of the Study:
- To evaluate the efficacy of a dual-acting gene therapy combining anti-VEGFA microRNAs and pigment endothelial-derived factor (PEDF) delivered via adeno-associated virus (AAV) vectors.
- To assess the protective effect of this dual therapy against CNV.
Main Methods:
- Engineered a multigenic AAV vector for retina pigment epithelium (RPE)-specific expression of anti-VEGFA miRNAs and PEDF.
- Validated PEDF expression in human cells and mouse retina using the RPE-specific vitelliform macular dystrophy 2 promoter.
- Utilized a laser-induced CNV mouse model to test AAV5-mediated dual therapy and monotherapy.
Main Results:
- Significant reduction in CNV was observed with both dual-acting therapy and anti-VEGFA miRNA monotherapy 57 days post-injection.
- The most prominent CNV reduction occurred in animals receiving the dual-acting therapy.
- Both therapeutic approaches led to a significant decrease in VEGFA levels.
Conclusions:
- Multigenic AAV vector-mediated gene therapy targeting VEGFA demonstrates combined efficacy.
- Dual-acting therapy represents a promising strategy for treating neovascular ocular diseases, including AMD.
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