Soluble VEGF receptor therapy for brain arteriovenous malformation

可溶性 VEGF 受体治疗脑动静脉畸形

基本信息

批准号：
8702392
负责人：
HUA SU
金额：
$ 39.44万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702392
关键词：
Adult Animal Model Antibody Therapy Arteriovenous malformation Avastin Binding Blood - brain barrier anatomy Blood Vessels Brain Brain Part Capsid Cardiac Output Case Study Choroidal Neovascularization Clinical Trials Coupling Data Development Dose Dysplasia Epistaxis Excision FLT1 gene Functional disorder Funding Future Gene Expression Glial Fibrillary Acidic Protein Goals Grant Headache Health Hemorrhage Hereditary hemorrhagic telangiectasia Injection of therapeutic agent Interruption Intracranial Hemorrhages Intravenous Intravenous infusion procedures Lasers Lead Lesion Liver Macular degeneration Maintenance Mediating Membrane Modality Modeling Monoclonal Antibodies Morbidity - disease rate National Institute of Neurological Disorders and Stroke Natural History Neuraxis Operative Surgical Procedures Pathology Patients Peritoneal Phase Phenotype Prevention Protein Tyrosine Kinase Radiation therapy Radiosurgery Risk Route Rupture Serotyping Signal Transduction Symptoms Telangiectasis Testing Tetracyclines Therapeutic Therapeutic Embolization Time Tissues Translational Research Treatment Efficacy U-Series Cooperative Agreements Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vitreous humor Workload adeno-associated viral vector angiogenesis base bevacizumab hemiparesis human disease indexing innovation intravenous injection model development mouse model nonhuman primate pre-clinical prevent programs promoter research clinical testing research study response vector

项目摘要

DESCRIPTION (provided by applicant): 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

描述（由申请人提供）：此申请是转化研究中的探索/发展项目的响应。目的是证明使用腺相关病毒载体（AAV）的初步疗效（可溶性FMS相关的酪氨酸激酶1（SFLT1），也称为血管内皮生长因子（VEGF）受体1，以治疗脑动脉动脉瘤畸形（BAVM）。脑AVM是颅内出血（ICH）的重要原因。可用的疗法潜在的发病率很高，由于风险过高，目前约有20％的患者未提供治疗。关于是否应使用侵入性方式处理破裂的BAVM也存在很大争议。过度的VEGF表达似乎是BAVM病理学的基本组成部分。令人信服的证据表明，VEGF信号的中断可能是一种治疗策略。有一份单例报道贝伐单抗（阿瓦斯汀，一种抗VEGF单克隆抗体）的治疗，导致立体定向放射术后出现头痛和偏瘫的BAVM患者的症状明显改善。重要的是，在BAVM表型的动物模型中，我们表明使用贝伐单抗的抗VEGF疗法减少了异常血管的数量。但是，抗体疗法有许多缺点，包括对诱导出血的担忧以及长时间间歇性静脉内（即）输注的需求。可溶性FLT（SFLT1）与组织中的VEGF结合并中和，从而通过膜结合的VEGFRS降低了其下游信号传导。在非人类灵长类动物模型中抑制了AAV血清型2 Capsid（AAV2）包装的AAV构建体中的可溶性FLT1，这导致了ME临床试验的黄斑变性试验（NCT01024998）。但是，AAV2不会越过血脑屏障（BBB）。我们希望使用血清型9通过非侵入性的方式通过非侵入性方式传递矢量（AAV9），因为AAV9更有效地进入了脑实质。该项目的总体目标是测试AAV9 CAPSID包装的AAV-SFLT的血管内输送是否会防止我们的BAVM表型模型中的异常血管表型的进展或逆转。一旦证明了SFLT治疗功效，我们将将AAV9载体与四环素反应和中枢神经系统（CNS）靶向启动子（例如神经胶质纤维纤维酸性蛋白的启动子）相结合，从而使基因表达的时间控制允许空间控制。从这项研究获得的关键初步数据将为成功的U01合作协议应用提供基础，该协议将制定创新的策略来实施人类疾病的治疗。最终，这项研究将导致临床前发展，这将使我们能够申请IND和早期临床试验