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

Gene Therapy volume 22, pages 893–900 (2015)Cite this article

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Abstract

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.

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Acknowledgements

We thank the members of the UCSF BAVM Study Project (http://avm.ucsf.edu) for their support, and Voltaire Gungab for assistance with manuscript preparation. This study was supported by grants to H. Su from the National Institutes of Health (R01 NS027713, R01 HL122774, and R21 NS070153) and from the Michael Ryan Zodda Foundation and UCSF Research Evaluation and Allocation Committee (REAC), and by a grant to F Shen from the National Natural Science Foundation of China (No 81471177).

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  1. F Shen and L Mao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, USA

    F Shen, L Mao, W Zhu & H Su

  2. Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    F Shen

  3. Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA

    M T Lawton

  4. Sanofi-Genzyme R&D Center, Framingham, MA, USA

    P Pechan & A Scaria

  5. Ocular Gene Therapy Core, National Eye Institute, National Institutes of Health, Bethesda, MD, USA

    P Colosi & Z Wu

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Correspondence to H Su.

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Shen, F., Mao, L., Zhu, W. et al. Inhibition of pathological brain angiogenesis through systemic delivery of AAV vector expressing soluble FLT1. Gene Ther 22, 893–900 (2015). https://doi.org/10.1038/gt.2015.57

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