Genome editing abrogates angiogenesis in vivo

被引：116

作者：

Huang, Xionggao ^{[1
,2
,3
]}

Zhou, Guohong ^{[1
,2
,4
]}

Wu, Wenyi ^{[1
,2
,5
]}

Duan, Yajian ^{[1
,2
,4
]}

Ma, Gaoen ^{[1
,2
]}

Song, Jingyuan ^{[1
,2
,6
,7
]}

Xiao, Ru ^{[1
,2
]}

Vandenberghe, Luk ^{[1
,2
]}

Zhang, Feng ^{[8
]}

D'Amore, Patricia A. ^{[1
,2
]}

Lei, Hetian ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Schepens Eye Res Inst, Massachusetts Eye & Ear, Boston, MA 02114 USA

[2] Harvard Med Sch, Dept Ophthalmol, Boston, MA 02114 USA

[3] Hainan Eye Hosp, Haikou 570311, Hainan, Peoples R China

[4] Shanxi Eye Hosp, Taiyuan 030002, Shanxi, Peoples R China

[5] Cent S Univ, Xiangya Hosp 2, Dept Ophthalmol, Changsha 410013, Hunan, Peoples R China

[6] Chinese Acad Med Sci, Inst Med Plant Dev, Beijing 100193, Peoples R China

[7] Peking Union Med Coll, Beijing 100193, Peoples R China

[8] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

美国国家卫生研究院;

关键词：

LEBERS CONGENITAL AMAUROSIS; GENE-THERAPY; PATHOLOGICAL ANGIOGENESIS; MACULAR DEGENERATION; CELLS; RECEPTOR; MOUSE; MODEL; CARCINOGENESIS; IDENTIFICATION;

D O I：

10.1038/s41467-017-00140-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：8

共 40 条

[1] Effect of gene therapy on visual function in Leber's congenital amaurosis [J].

Bainbridge, James W. B. ;

Smith, Alexander J. ;

Barker, Susie S. ;

Robbie, Scott ;

Henderson, Robert ;

Balaggan, Kamaljit ;

Viswanathan, Ananth ;

Holder, Graham E. ;

Stockman, Andrew ;

Tyler, Nick ;

Petersen-Jones, Simon ;

Bhattacharya, Shomi S. ;

Thrasher, Adrian J. ;

Fitzke, Fred W. ;

Carter, Barrie J. ;

Rubin, Gary S. ;

Moore, Anthony T. ;

Ali, Robin R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (21) :2231-2239

[2] Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis [J].

Bergers, G ;

Brekken, R ;

McMahon, G ;

Vu, TH ;

Itoh, T ;

Tamaki, K ;

Tanzawa, K ;

Thorpe, P ;

Itohara, S ;

Werb, Z ;

Hanahan, D .

NATURE CELL BIOLOGY, 2000, 2 (10) :737-744

[3] Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial [J].

Chakravarthy, Usha ;

Harding, Simon P. ;

Rogers, Chris A. ;

Downes, Susan M. ;

Lotery, Andrew J. ;

Culliford, Lucy A. ;

Reeves, Barnaby C. .

LANCET, 2013, 382 (9900) :1258-1267

[4] Exploring the Molecular Interactions of 7,8-Dihydroxyflavone and Its Derivatives with TrkB and VEGFR2 Proteins [J].

Chitranshi, Nitin ;

Gupta, Vivek ;

Kumar, Sanjay ;

Graham, Stuart L. .

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2015, 16 (09) :21087-21108

[5] Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis [J].

Connor, Kip M. ;

Krah, Nathan M. ;

Dennison, Roberta J. ;

Aderman, Christopher M. ;

Chen, Jing ;

Guerin, Karen I. ;

Sapieha, Przemyslaw ;

Stahl, Andreas ;

Willett, Keirnan L. ;

Smith, Lois E. H. .

NATURE PROTOCOLS, 2009, 4 (11) :1565-1573

[6] Therapeutic genome editing: prospects and challenges [J].

Cox, David Benjamin Turitz ;

Platt, Randall Jeffrey ;

Zhang, Feng .

NATURE MEDICINE, 2015, 21 (02) :121-131

[7] Identification of synthetic endothelial cell-specific promoters by use of a high-throughput screen [J].

Dai, C ;

McAninch, RE ;

Sutton, RE .

JOURNAL OF VIROLOGY, 2004, 78 (12) :6209-6221

[8]

Deyle DR, 2009, CURR OPIN MOL THER, V11, P442

[9] The Clustered, Regularly Interspaced, Short Palindromic Repeats-associated Endonuclease 9 (CRISPR/Cas9)-created MDM2 T309G Mutation Enhances Vitreous-induced Expression of MDM2 and Proliferation and Survival of Cells [J].

Duan, Yajian ;

Ma, Gaoen ;

Huang, Xionggao ;

D'Amore, Patricia A. ;

Zhang, Feng ;

Lei, Hetian .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (31) :16339-16347

[10] A survey of ex vivo/in vitro transduction efficiency of mammalian primary cells and cell lines with Nine natural adeno-associated virus (AAV1-9) and one engineered adeno-associated virus serotype [J].

Ellis, Brian L. ;

Hirsch, Matthew L. ;

Barker, Jenny C. ;

Connelly, Jon P. ;

Steininger, Robert J., III ;

Porteus, Matthew H. .

VIROLOGY JOURNAL, 2013, 10

← 1 2 3 4 →