Josephine Natalia E S Benckendorff

Suppression of Choroidal Neovascularization by AAV-Based Dual-Acting Antiangiogenic Gene Therapy

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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.

Original languageEnglish
JournalMolecular Therapy - Nucleic Acids
Pages (from-to)38-50
Number of pages13
Publication statusPublished - 7 Jun 2019

    Research areas

  • adeno-associated virus, age-related macular degeneration, choroidal neovascularization, dual-acting therapy, retina pigment epithelium, vascular endothelial growth factor A

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