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Nat Commun. 2017 Jul 24;8(1):112. doi: 10.1038/s41467-017-00140-3.

Genome editing abrogates angiogenesis in vivo.

Huang X1,2,3, Zhou G1,2,4, Wu W1,2,5, Duan Y1,2,4, Ma G1,2, Song J1,2,6, Xiao R1,2, Vandenberghe L1,2, Zhang F7, D'Amore PA1,2, Lei H8,9.

Author information

1
Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA.
2
Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA.
3
Hainan Eye Hospital, Haikou, Hainan Province, 570311, China.
4
Shanxi Eye Hospital, Taiyuan, Shanxi Province, 030002, China.
5
Department of Ophthalmology, Second Xiangya Hospital, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013, China.
6
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, China.
7
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02142, USA.
8
Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA. hetian_lei@meei.harvard.edu.
9
Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. hetian_lei@meei.harvard.edu.

Abstract

Angiogenesis, in which vascular endothelial growth factor receptor (VEGFR) 2 plays an essential role, is associated with a variety of human diseases including proliferative diabetic retinopathy and wet age-related macular degeneration. Here we report that a system of adeno-associated virus (AAV)-mediated clustered regularly interspaced short palindromic repeats (CRISPR)-associated endonuclease (Cas)9 from Streptococcus pyogenes (SpCas9) is used to deplete VEGFR2 in vascular endothelial cells (ECs), whereby the expression of SpCas9 is driven by an endothelial-specific promoter of intercellular adhesion molecule 2. We further show that recombinant AAV serotype 1 (rAAV1) transduces ECs of pathologic vessels, and that editing of genomic VEGFR2 locus using rAAV1-mediated CRISPR/Cas9 abrogates angiogenesis in the mouse models of oxygen-induced retinopathy and laser-induced choroid neovascularization. This work establishes a strong foundation for genome editing as a strategy to treat angiogenesis-associated diseases.Abnormal angiogenesis causes many ocular diseases. Here the authors employ CRISPR/Cas9 gene editing technology to silence VEGFR2, a major regulator of angiogenesis, in retinal endothelium and abrogate angiogenesis in the mouse models of oxygen-induced retinopathy and laser-induced choroid neovascularization.

PMID:
28740073
PMCID:
PMC5524639
DOI:
10.1038/s41467-017-00140-3
[Indexed for MEDLINE]
Free PMC Article

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