This application is a response the call, PAR-13-023 Exploratory/Developmental Projects in Translational Research. The goal is to demonstrate the preliminary efficacy of using adeno-associated viral vector (AAV) - mediated expression of soluble FMS-related tyrosine kinase 1 (sFLT1), also called vascular endothelial growth factor (VEGF) receptor-1, for the treatment of brain arteriovenous malformations (bAVM). Brain AVM is an important cause of intracranial hemorrhage (ICH). Available therapies have potentially high morbidity, and due to excessive risk, about 20% of patients are currently not offered treatment. There is also considerable controversy over whether ruptured bAVMs should be treated using invasive modalities. Excessive VEGF expression seems to be a fundamental part of the bAVM pathology. Compelling evidence show interruption of VEGF signaling could be a therapeutic strategy. There is a single-case report of bevacizumab (Avastin, an anti-VEGF monoclonal antibody) treatment resulting in marked improvement in the symptoms of a bAVM patient who had developed headaches and hemiparesis after stereotactic radiosurgery. Importantly, in an animal model of the bAVM phenotype, we showed that anti-VEGF therapy with bevacizumab reduced the number of abnormal vessels. However, antibody therapy has many drawbacks, including concerns over inducing hemorrhage and the need for prolonged periods of intermittent intravenous (i.e.) infusions. Soluble FLT (sFLT1) binds to and neutralizes VEGF in the tissue, thus reducing its downstream signaling through membrane-bound VEGFRs. Soluble FLT1 in an AAV construct packaged in AAV serotype 2 capsid (AAV2) inhibited choroid neovascularization in a non-human primate model, which has led to a Phase Me clinical trial for macular degeneration (NCT01024998). However, AAV2 does not cross the blood-brain barrier (BBB). We wish to deliver the vector through a non-invasive manner, intravenously or intra-arterially, using serotype 9 to package the vector (AAV9), because AAV9 enters the brain parenchyma much more effectively. The overarching goal of the project is to test if intravascular delivery of AAV-sFLT packaged in AAV9 capsid will prevent progression of or reverse the abnormal vascular phenotype in our bAVM phenotype models. Once the sFLT therapeutic efficacy is proved, we will couple the AAV9 vector to a tetracycline-response and central nervous system (CNS)-targeted promoter (e.g., promoter of glial fibrillary acidic protein), which allow spatial an temporal control of gene expression. Key preliminary data obtained from this study will provide the basis for a successful U01 cooperative agreement application, which will develop an innovative strategy to implement therapy for the human disease. Ultimately, this study will result in preclinical developments that will allow us to apply for an IND and early- phase clinical trials

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Koenig, James I
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Wei, Meng; Lyu, Haiyian; Huo, Kang et al. (2018) Impact of Bone Fracture on Ischemic Stroke Recovery. Int J Mol Sci 19:
Zhang, Meng; Deng, Yong-Ning; Zhang, Jing-Yi et al. (2018) SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway. Aging Dis 9:273-286
Zhu, Wan; Ma, Li; Zhang, Rui et al. (2017) The roles of endoglin gene in cerebrovascular diseases. Neuroimmunol Neuroinflamm 4:199-210
Zhu, Wan; Shen, Fanxia; Mao, Lei et al. (2017) Soluble FLT1 Gene Therapy Alleviates Brain Arteriovenous Malformation Severity. Stroke 48:1420-1423
Zou, Dingquan; Luo, Man; Han, Zhenying et al. (2017) Activation of Alpha-7 Nicotinic Acetylcholine Receptor Reduces Brain Edema in Mice with Ischemic Stroke and Bone Fracture. Mol Neurobiol 54:8278-8286
Ma, Li; Kim, Helen; Chen, Xiao-Lin et al. (2017) Morbidity after Hemorrhage in Children with Untreated Brain Arteriovenous Malformation. Cerebrovasc Dis 43:231-241
Ma, Li; Shen, Fanxia; Jun, Kristine et al. (2016) Integrin ?8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice. Transl Stroke Res 7:488-496
Zhang, Rui; Han, Zhenying; Degos, Vincent et al. (2016) Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation. Angiogenesis 19:451-461
Zhang, Rui; Zhu, Wan; Su, Hua (2016) Vascular Integrity in the Pathogenesis of Brain Arteriovenous Malformation. Acta Neurochir Suppl 121:29-35
Huo, Kang; Hashim, Syed I; Yong, Kimberley L Y et al. (2016) Impact and risk factors of post-stroke bone fracture. World J Exp Med 6:1-8

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