Soluble VEGF receptor therapy for brain arteriovenous malformation

描述（由申请人提供）：本申请是对PAR-13-023转化研究中的探索/开发项目的响应。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（sFLT 1）（也称为血管内皮生长因子（VEGF）受体-1）表达治疗脑动静脉畸形（bAVM）的初步疗效。脑动静脉畸形是颅内出血的重要原因。现有的治疗具有潜在的高发病率，并且由于过度的风险，目前约20%的患者未被提供治疗。对于破裂的bAVM是否应该使用侵入性方式进行治疗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，中断VEGF信号可能是一种治疗策略。有一份贝伐珠单抗（安维汀，一种抗VEGF单克隆抗体）治疗的单一病例报告，导致立体定向放射外科手术后出现头痛和轻偏瘫的bAVM患者的症状显著改善。重要的是，在bAVM表型的动物模型中，我们发现贝伐单抗VEGF治疗减少了异常血管的数量。然而，抗体疗法有许多缺点，包括担心诱导出血和需要长时间的间歇性静脉内（即，输液可溶性FLT（sFLT 1）与组织中的VEGF结合并中和，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（AAV 2）中的AAV构建体中的可溶性FLT 1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（NCT 01024998）。然而，AAV 2不穿过血脑屏障（BBB）。我们希望使用血清型9包装载体（AAV 9）通过非侵入性方式静脉内或动脉内递送载体，因为AAV 9更有效地进入脑实质。该项目的首要目标是测试包装在AAV 9衣壳中的AAV-sFLT的血管内递送是否会阻止我们的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AAV 9载体偶联至四环素应答和中枢神经系统（CNS）靶向启动子（例如，胶质细胞酸性蛋白启动子），其允许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成功的U 01合作协议申请提供基础，这将开发一种创新策略来实施人类疾病的治疗。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

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