期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 16, 期 -, 页码 38-50出版社
CELL PRESS
DOI: 10.1016/j.omtn.2019.01.012
关键词
-
资金
- Faculty of Health Sciences
- Danish Council for Independent Research [4183-00017B]
- Gene Therapy Initiative Aarhus (GTI-Aarhus) - Lundbeck Foundation [R126-2012-12456]
- Lundbeck Foundation [R165-2013-15631]
- Danish Eye Research Foundation
- Aase og Ejnar Danielsen's Foundation
- Kobmand Marie Kirstine Jensens Fond
- Riisfort Foundation
- Svend Helge Schroder og hustru Ketty Lydia Larsen Schroders fond
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据