Soluble VEGF receptor therapy for brain arteriovenous malformation

可溶性 VEGF 受体治疗脑动静脉畸形

• 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
• 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

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）：本申请是对 PAR-13-023 转化研究探索/开发项目号召的响应。目的是证明使用腺相关病毒载体 (AAV) 介导的可溶性 FMS 相关酪氨酸激酶 1 (sFLT1)（也称为血管内皮生长因子 (VEGF) 受体-1）的表达治疗脑动静脉畸形 (bAVM) 的初步疗效。脑AVM是颅内出血（ICH）的重要原因。现有疗法具有潜在的高发病率，并且由于风险过高，目前约有 20% 的患者未获得治疗。关于破裂的脑动静脉畸形是否应该采用侵入性治疗方式也存在相当大的争议。 VEGF 过度表达似乎是 bAVM 病理学的基本组成部分。令人信服的证据表明，阻断 VEGF 信号传导可能是一种治疗策略。有一个单例报告，贝伐珠单抗（Avastin，一种抗 VEGF 单克隆抗体）治疗使一位 bAVM 患者在立体定向放射外科手术后出现头痛和偏瘫的症状得到显着改善。重要的是，在 bAVM 表型的动物模型中，我们发现贝伐珠单抗抗 VEGF 治疗减少了异常血管的数量。然而，抗体疗法有许多缺点，包括担心诱发出血以及需要长时间间歇性静脉（即）输注。可溶性 FLT (sFLT1) 结合并中和组织中的 VEGF，从而减少其通过膜结合 VEGFR 的下游信号传导。包装在 AAV 血清型 2 衣壳 (AAV2) 中的 AAV 构建体中的可溶性 FLT1 可抑制非人灵长类动物模型中的脉络膜新生血管形成，这导致了黄斑变性的 Me 期临床试验 (NCT01024998)。然而，AAV2 不能穿过血脑屏障 (BBB)。我们希望通过静脉内或动脉内的非侵入性方式传递载体，使用血清型9包装载体（AAV9），因为AAV9更有效地进入脑实质。该项目的总体目标是测试包装在 AAV9 衣壳中的 AAV-sFLT 的血管内递送是否会阻止 bAVM 表型模型中异常血管表型的进展或逆转。一旦sFLT治疗功效得到证实，我们将把AAV9载体与四环素反应和中枢神经系统（CNS）靶向启动子（例如神经胶质原纤维酸性蛋白启动子）偶联，从而实现基因表达的空间和时间控制。从这项研究中获得的关键初步数据将为U01合作协议的成功申请提供基础，该协议将制定一种创新策略来实施人类疾病的治疗。最终，这项研究将带来临床前开发，使我们能够申请 IND 和早期临床试验