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: 7246535
• 负责人: Valder R. Arruda
• 金额: $ 36.24万
• 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/7246535
• 关键词: Adult; Affect; Animals; Antibodies; Antibody Formation; Antigens; Arteries; Autoimmune Diseases; Benign; Biodistribution; Biological; Biological Assay; Biopsy; Blood Circulation; Blood Coagulation Factor; Canis familiaris; Capsid; Cells; Chemistry, Other; Childhood; Clinical; Clinical Research; Clinical Trials; Condition; Cytomegalovirus; Daily; Data; Disease; Dose; Elevation; Enrollment; Enzymes; Exposure to; Factor IX; Figs - dietary; Frequencies; Funding; Gene Delivery; Gene Transfer; Genes; Goals; Hemophilia A; Hemophilia B; Hemorrhage; Hepatic; Hepatic artery; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; Immune response; Immune system; Immunosuppressive Agents; Infection; Infusion procedures; Inherited; Injection of therapeutic agent; Injury; Intervention; Life; Link; Liver; Lymphoid Cell; Measures; Mediating; Memory; Modeling; Modification; Monitor; Mus; Muscle; Mycophenolate Mofetil/Tacrolimus; Organ Transplantation; Oryctolagus cuniculus; Patients; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Phase; Plasma; Population; Proteins; Protocols documentation; Rattus; Recombinants; Research Personnel; Residual state; Resolution; Role; Route; Safety; Serious Adverse Event; Serotyping; Skeletal Muscle; Source; Standards of Weights and Measures; T-Lymphocyte; Tacrolimus; Testing; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Toxic effect; Transaminases; Transplant Recipients; Treatment Protocols; Viral; Viral Vector; Week; Work; base; cellular transduction; cohort; experience; expression vector; falls; immunoregulation; inhibitor/antagonist; intrahepatic; male; mycophenolate mofetil; neutralizing antibody; nonhuman primate; preclinical study; prevent; programs; transgene expression; transmission process; 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）： B 型血友病是一种遗传性出血性疾病，其特征是缺乏 IX 因子 (F.IX)。该疾病是基因治疗的绝佳候选者，因为 F.IX 低至正常值的 1-5% 即可带来临床益处。 IAAV-2（肝脏定向 F.IX 基因转移至血友病 B 受试者）的 I/II 期临床研究于 4 年前启动。总体而言，通过肝动脉的载体递送耐受性良好，没有发生严重的不良事件。高剂量组中的一名受试者在接受载体后两周内循环 F.IX 水平为正常值的 12%，但表达时间短暂。表达丧失伴随着无症状的转氨炎，但可自行缓解。免疫介导的转导肝细胞破坏很可能是导致转氨炎和表达缺失的原因。为了避免这种情况的发生，我们将测试免疫调节是否允许在不损伤肝细胞的情况下表达。这项工作的总体目标是确定吗替麦考酚酯 (MMF) 和他克莫司 (TC) 短暂免疫抑制方案对 AAV-2-F.IX 的有效性和安全性。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中进行了长期免疫抑制治疗的广泛测试。在目标 1 中，我们将使用最接近人类的非人类灵长类动物模型 (NHP) 来确定 MMF/TC 方案对 AAV-2 肝脏定向基因转移的有效性和安全性。由于这些药物可能干扰双链 DMA 合成，我们将通过在 NHP 中注射 AAV-2 来确定 MMF/TC 是否会干扰基因转移/转基因表达、载体衣壳在肝组织中的持续时间以及载体生物分布。该结果将为一项新的剂量递增 I/II 期临床研究提供基础，该研究涉及 AAV-2 介导的肝脏直接 F.IX 基因递送至成人 B 型血友病受试者（目标 2-4）。我们的主要目标是通过监测受试者的局部和全身毒性、载体生物分布以及 F.IX 抗体形成来确定该方法的安全性。具体来说，我们将表征 AAV-2 衣壳中和抗体在阻止 AAV-2 转导中的作用，定义对 AAV 衣壳肽的免疫反应，并确定所需免疫调节的持续时间。我们还计划通过测量 F.IX 的生物活性来评估每个受试者的潜在功效。