FIX Hepatic Gene Therapy Transfer Under Immunomodulation

免疫调节下的 FIX 肝基因治疗转移

• 批准号: 7154983
• 负责人: Valder Arruda
• 金额: $ 11.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154983
• 关键词: FK506; Macaca fascicularis; Macaca mulatta; antibody; biotechnology; blood disorder chemotherapy; cooperative study; gene delivery system; gene therapy; hemophilia As; hemophilia B; human subject; immunomodulators; immunosuppression; liver cells; mycophenolate mofetil; nonhuman therapy evaluation; patient oriented research; transfection

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 lemophilia B subjects was initiated 4 years ago. Overall the vector delivery through the hepatic artery was well derated 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 DNA synthesis we will determine f MMF/TC will interfere with gene transfer/transgene expression, duration of the vector capsid persistence, in he 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 nemophilia 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. Both preclinical and clinical experiments proposed here will provide useful information not only for the AAV-2 mediated gene transfer but also for experiments proposed in Project 5 of this PEGT.

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年前开始了一项关于IAAV-2的相位L/LL临床研究，肝脏定向的F.IX基因转移到Lemophilia B受试者。总体而言，通过肝动脉传递的矢量递送毫无疑问，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。很有可能 免疫介导的转导肝细胞的破坏是跨动脉炎和表达丧失的原因。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），这是与人类最接近的模型，以在AAV-2静电驾驶方向上建立MMF/TC方案的功效和安全性 基因转移。由于这些药物可能会干扰双链DNA合成，因此我们将确定F MMF/TC会干扰基因转移/转基因表达，在He He He肝组织中，并在NHP中注入AAV-2。结果将为AAV-2介导的肝直接f.ix基因递送到成年嗜性嗜性B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。具体来说，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的持续时间。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。此处提出的临床前和临床实验都将不仅为AAV-2介导的基因转移提供有用的信息，而且还为该PEGT项目5中提出的实验提供了有用的信息。