AAV2-F.IX Hepatic Gene Transfer under Immunomodulation

免疫调节下的 AAV2-F.IX 肝基因转移

• 批准号: 7078208
• 负责人: Valder R. Arruda
• 金额: $ 38.04万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-13 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7078208
• 关键词: FK506; Macaca fascicularis; Macaca mulatta; adeno associated virus group; artificial immunosuppression; capsid; communicable disease transmission; disease /disorder proneness /risk; dosage; gene expression; hemophilia B; human subject; human therapy evaluation; immune response; immunogenetics; liver; mycophenolate mofetil; nonhuman therapy evaluation; patient oriented research; recombinant virus; transfection /expression vector

DESCRIPTION (provided by applicant): Hemophilia B is a inherited bleeding disorder characterized by a deficiency of factor IX (F.IX). The disease is an excellent candidate for treatment by gene-based therapy because F.IX as low as 1-5% of normal is associated with clinical benefits. A Phase l/ll clinical study on IAAV-2, liver-directed F.IX gene transfer to hemophilia B subjects was initiated 4 years ago. Overall the vector delivery through the hepatic artery was well tolerated with no serious adverse event. One subject in the high dose group had circulating F. IX levels of 12% of normal 2 weeks after receiving vector, but expression was short lived. The loss of expression was accompanied by an asymptomatic transaminitis that resolved spontaneously. There is high likelihood that immune-mediated destruction of the transduced hepatocytes was responsible for transaminitis and loss of expression. To circumvent this occurrence, we will test whether immunomodulation allows expression without hepatocyte damage. The overall goal of this work is to establish the efficacy and safety of a transient immunosuppressive regimen with mycophenolate mofetil (MMF) and tacrolimus (TC) on AAV-2-F.IX. The regimen consisting of MMF/TC has been extensively tested for long-term immune-suppressive therapy in organ transplant recipients and subjects with autoimmune diseases. In aim 1 we will use non-human primates (NHP), the closest model to human to establish the efficacy and safety of MMF/TC regimen on AAV-2-liver-directed gene transfer. Because these drugs may interfere with double strand DMA synthesis we will determine if MMF/TC will interfere with gene transfer/transgene expression, duration of the vector capsid persistence, in the liver tissue and with vector biodistribution by injecting AAV-2 in NHP. The results will provide the basis for a new dose escalation Phase l/ll clinical study on AAV-2-mediated, liver-direct F.IX gene delivery to adult hemophilia B subjects (aims 2-4). Our main goal is to determine the safety of this approach by monitoring subjects for local and systemic toxicity, vector biodistribution, and for antibody formation to F.IX. Specifically, we will characterize the role of neutralizing antibody to AAV-2 capsid on preventing AAV-2 transduction, will define the immune responses to AAV capsid peptides,,and determine the duration of the immunomodulation required. We also plan to evaluate the potential efficacy in each subject by measuring biological activity of F. IX.

描述（由申请人提供）： 血友病B是一种遗传性出血障碍，其特征是因子IX（f.ix）缺乏。该疾病是通过基于基因治疗的候选者的出色候选者，因为F.IX低至正常的1-5％与临床益处有关。 4年前开始了对IAAV-2的L/LL临床研究，肝脏定向的F.IX基因转移到血友病B受试者。总体而言，通过肝动脉的载体传递良好，没有严重的不良事件。高剂量组中的一个受试者的循环f。表达的丧失伴随着无症状的透射炎，该透明炎自发解决。免疫介导的转导肝细胞的破坏很可能导致跨氨基炎和表达丧失。为了避免这种情况，我们将测试免疫调节是否允许无肝细胞损伤的表达。这项工作的总体目标是在AAV-2-f.ix上建立瞬时免疫抑制方案的功效和安全性。由MMF/TC组成的方案已在器官移植受者和患有自身免疫性疾病的受试者的长期免疫抑制治疗中进行了广泛的测试。在AIM 1中，我们将使用非人类灵长类动物（NHP），这是最接近人类的模型，以建立MMF/TC方案在AAV-2肝导向基因转移上的功效和安全性。由于这些药物可能会干扰双链DMA合成，因此我们将确定MMF/TC是否会干扰基因转移/转基因表达，肝组织中的载体capsid持久性的持续时间，并在NHP中注入AAV-2，并将其注入AAV-2。结果将为AAV-2介导的肝直接f.ix基因递送至成年血友病受试者的新剂量升级阶段L/LL临床研究提供基础（AIMS 2-4）。我们的主要目标是通过监测对象的局部和系统毒性，向量生物分布以及抗体形成f.ix来确定这种方法的安全性。具体而言，我们将表征中和对AAV-2衣壳在防止AAV-2转导的作用，将定义对AAV CAPSID肽的免疫反应，并确定所需的免疫调节持续时间。我们还计划通过测量F. ix的生物学活性来评​​估每个受试者的潜在疗效。