Inhibition of pathological brain angiogenesis through systemic delivery of AAV vector expressing soluble FLT1

被引：5

作者：

Shen, F. ^{[1
,2
]}

Mao, L. ^{[1
]}

Zhu, W. ^{[1
]}

Lawton, M. T. ^{[3
]}

Pechan, P. ^{[4
]}

Colosi, P. ^{[5
]}

Wu, Z. ^{[5
]}

Scaria, A. ^{[4
]}

Su, H. ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, Ctr Cerebrovasc Res, San Francisco, CA 94110 USA

[2] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Neurol, Shanghai, Peoples R China

[3] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94110 USA

[4] Sanofi Genzyme R&D Ctr, Framingham, MA USA

[5] NEI, Ocular Gene Therapy Core, NIH, Bethesda, MD 20892 USA

来源：

GENE THERAPY | 2015年 / 22卷 / 11期

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

ENDOTHELIAL GROWTH-FACTOR; HEREDITARY HEMORRHAGIC TELANGIECTASIA; ADULT-MOUSE BRAIN; ADENOASSOCIATED VIRUS; GENE-TRANSFER; ARTERIOVENOUS-MALFORMATION; VASCULAR MALFORMATIONS; IMMUNE-RESPONSES; VEGF; THERAPY;

D O I：

10.1038/gt.2015.57

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The soluble vascular endothelial growth factor (VEGF) receptor 1 (sFLT1) has been tested in both animals and humans for anti-angiogenic therapies, for example, age-related macular degeneration. We hypothesized that adeno-associated viral vector (AAV)mediated sFLT1 expression could be used to inhibit abnormal brain angiogenesis. We tested the anti-angiogenic effect of sFLT1 and the feasibility of using AAV serotype 9 to deliver sFLT1 through intravenous injection (IV) to the brain angiogenic region. AAVs were packaged in AAV serotypes 1 and 2 (stereotactic injection) and 9 (IV injection). Brain angiogenesis was induced in adult mice through stereotactic injection of AAV1-VEGF. AAV2-sFLT02 containing sFLT1 VEGF-binding domain (domain 2) was injected into the brain angiogenic region, and AAV9-sFLT1 was injected into the jugular vein at the time of or 4 weeks after AAV1-VEGF injection. We showed that AAV2-sFLT02 inhibited brain angiogenesis at both time points. IV injection of AAV9-sFLT1 inhibited angiogenesis only when the vector was injected 4 weeks after angiogenic induction. Neither lymphocyte infiltration nor neuron loss was observed in AAV9-sFLT1-treated mice. Our data show that systemically delivered AAV9-sFLT1 inhibits angiogenesis in the mouse brain, which could be utilized to treat brain angiogenic diseases such as brain arteriovenous malformation.

引用

页码：893 / 900

页数：8

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