Immune Barriers to AAV Gene Therapy

AAV 基因治疗的免疫障碍

• 批准号: 7802296
• 负责人: James M Wilson
• 金额: $ 14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802296
• 关键词: Address; Adenoviruses; Animals; Antigen Targeting; Biodistribution; Biology; Capsid; Cells; Clinical; Clinical Research; Clinical Trials; Complement; Complementary DNA; Data; Dependovirus; Disease; Enrollment; Evaluation; Family; Gene Transfer; Generations; Genome; Hepatocyte; Human; Immune; Immunity; Immunization; Immunologics; Infection; Inflammation; Liver; Macaca; Memory; Methods; Molecular; Morphology; Mus; Mutation; Natural Immunity; Open Reading Frames; Organ; Ornithine Carbamoyltransferase; Ornithine carbamoyltransferase deficiency; Pathway interactions; Performance; Phase I Clinical Trials; Population; Predisposition; Primates; Process; Research; Risk; Role; Safety; Series; Serotyping; System; T memory cell; T-Cell Activation; T-Lymphocyte; TLR3 gene; Tissues; Toxic effect; Transgenes; adeno-associated viral vector; base; clinical application; follow-up; gene therapy; improved; in vivo; mature animal; mouse model; nonhuman primate; novel; pre-clinical; preclinical study; promoter; research study; response; transgene expression; urea cycle; vector; vector genome

PROJECT I - IMMUNE BARRIERS TO AAV GENE THERAPY The performance of novel AAV serotypes, with the use of the self complementing genome, has vastly improved the prospects of successful liver-directed in vivo gene therapy. Despite these encouraging data, a number of potential barriers remain, primarily focused on the immunologic biology of in vivo gene therapy. This project will systemically address the immunologic response to in vivo gene therapy of novel AAVs as a prerequisite to their considerations in clinical applications. The first specific aim will focus on the identification of a clinical candidate which is defined as the actual vector to be considered in the Phase 1 clinical trial. The two components of the vector that will be extensively studied and optimized are: 1) the capsid, evaluated for efficiency and stability of gene transfer, toxicity, transgene and capsid T cells, pre-existing immunity and biodistribution; and 2) the genome, evaluated for peak and onset of expression. The second specific aim will analyze the role of pre-existing T cells to AAV capsids in terms of the safety and efficacy of liver-directed gene transfer. The third specific aim will evaluate the role of the target organ in eliciting problematic immunologic responses, specifically focusing on activation of innate immunity or inflammation. These studies will focus on murine systems in establishing basic principles which are followed up selectively in nonhuman primates. The project will extensively use the Vector and Morphology Cores and will collaborate directly with Project II on the evaluation of vector efficacy in the OTC-deficient mouse model and with Project III by providing NHP tissue for molecular characterization. Lay description. A vector of use for the treatment of OTC deficiency called the clinical candidate will be created. Potential immunologic responses of the recipient to the vector will be studied.

项目I- AAV基因疗法的免疫障碍 通过使用自我补充基因组，新颖的AAV血清型的表现非常 改善了成功的肝脏在体内基因治疗中的前景。尽管这些令人鼓舞的数据，但 潜在障碍的数量仍然存在，主要集中于体内基因治疗的免疫学生物学。 该项目将系统地解决新型AAV的体内基因疗法的免疫学反应 他们在临床应用中考虑的先决条件。第一个具体目标将重点放在身份证上 临床候选者的定义为在第一阶段临床试验中要考虑的实际载体。这 将经过广泛研究和优化的向量的两个组成部分是：1）CAPSID，评估 基因转移，毒性，转基因和衣壳T细胞的效率和稳定性，预先存在免疫力和 生物分布； 2）基因组，评估表达的峰值和发作。第二个特定目标将 根据肝脏指导的安全性和功效，分析现有的T细胞对AAV衣壳的作用 基因转移。第三个特定目的将评估目标器官在引起有问题的问题中的作用 免疫反应，特别关注先天免疫或炎症的激活。这些 研究将侧重于建立基本原理的鼠系统，这些原理有选择性地跟踪 非人类灵长类动物。该项目将广泛使用矢量和形态核心，并将合作 直接使用项目II进行评估，以评估OTC缺陷鼠标模型中的向量功效和项目 III通过提供NHP组织的分子表征。 外行描述。用于治疗OTC缺乏症的使用向量称为临床候选者 创建。将研究接受者对载体的潜在免疫反应。