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: 8833344
• 负责人: HUA SU
• 金额: $ 39.59万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833344
• 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(申请人提供)：此申请是对PAR-13-023翻译研究中的探索/发展项目的响应。目的是证明腺相关病毒载体(AAV)介导的可溶性FMS相关酪氨酸激酶1(SFlt1)(又称血管内皮生长因子(VEGF)受体1)治疗脑动静脉畸形(BAVM)的初步疗效。脑动静脉畸形是导致颅内出血的重要原因。现有的治疗方法具有潜在的高发病率，而且由于风险过高，目前约有20%的患者没有得到治疗。对于破裂的动静脉动静脉畸形是否应该使用侵入性方式进行治疗，也存在相当大的争议。血管内皮生长因子的过度表达似乎是bAVM病理的一个基本部分。令人信服的证据表明，阻断血管内皮生长因子信号转导可能是一种治疗策略。有一个单一病例的报告，贝伐单抗(阿瓦斯丁，一种抗血管内皮生长因子的单抗)治疗导致bAVM患者的症状显著改善，该患者在立体定向放射外科治疗后出现头痛和偏瘫。重要的是，在bAVM表型的动物模型中，我们显示贝伐单抗抗血管内皮生长因子治疗减少了异常血管的数量。然而，抗体疗法有许多缺点，包括担心导致出血，以及需要长时间间歇静脉注射(即)。输液。可溶性Flt(SFlt1)与组织中的血管内皮生长因子结合并中和，从而通过膜结合的VEGFRs减少其下游信号转导。包装在AAV血清2型衣壳(AAV2)中的AAV构建体中的可溶性Flt1抑制了非人灵长类动物模型中的脉络膜新生血管，这导致了黄斑变性的Me期临床试验(NCT01024998)。然而，AAV2不能通过血脑屏障(BBB)。我们希望通过一种非侵入性的方式传递载体，静脉或动脉内，使用9型血清包装载体(AAV9)，因为AAV9更有效地进入脑实质。该项目的首要目标是测试在AAV9衣壳内包装的AAV-sFlt血管内递送是否能够防止或逆转我们的bAVM表型模型中异常的血管表型。一旦sflt的治疗效果得到证实，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，胶质纤维酸性蛋白的启动子)偶联，从而实现对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，这将制定一项实施人类疾病治疗的创新战略。最终，这项研究将导致临床前的发展，使我们能够申请IND和早期临床试验