Cas9
脉络膜新生血管
清脆的
离体
血管内皮生长因子A
黄斑变性
亚基因组mRNA
视网膜
视网膜色素上皮
血管生成
医学
生物
血管内皮生长因子受体
体内
细胞生物学
血管内皮生长因子
癌症研究
眼科
遗传学
基因
生物化学
作者
Sikai Ling,Shiqi Yang,Xinde Hu,Di Yin,Yao Dai,Xiaoqing Qian,Dawei Wang,Xiaoyong Pan,Jiaxu Hong,Xiaodong Sun,Hui Yang,Søren R. Paludan,Yujia Cai
标识
DOI:10.1038/s41551-020-00656-y
摘要
Therapeutic genome editing requires effective and targeted delivery methods. The delivery of Cas9 mRNA using adeno-associated viruses has led to potent in vivo therapeutic efficacy, but can cause sustained Cas9 expression, anti-Cas9 immune responses and off-target edits. Lentiviral vectors have been engineered to deliver nucleases that are expressed transiently, but in vivo evidence of their biomedical efficacy is lacking. Here, we show that the lentiviral codelivery of Streptococcus pyogenes Cas9 mRNA and expression cassettes that encode a guide RNA that targets vascular endothelial growth factor A (Vegfa) is efficacious in a mouse model of wet age-related macular degeneration induced by Vegfa. A single subretinal injection of engineered lentiviruses knocked out 44% of Vegfa in retinal pigment epithelium and reduced the area of choroidal neovascularization by 63% without inducing off-target edits or anti-Cas9 immune responses. Engineered lentiviruses for the transient expression of nucleases may form the basis of new treatments for retinal neovascular diseases.
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