Immune Barriers to AAV Gene Therapy

项目I-AAV基因治疗的免疫障碍 新的AAV血清型的表现，通过使用自我互补的基因组，已经有了巨大的 提高了成功的肝脏导向体内基因治疗的前景。尽管有这些令人鼓舞的数据，但 一些潜在的障碍仍然存在，主要集中在体内基因治疗的免疫生物学上。 该项目将系统地研究新型AAVs体内基因治疗的免疫学反应。 临床应用时考虑的前提条件。第一个具体目标将集中在识别 被定义为在第一阶段临床试验中要考虑的实际载体的临床候选。这个 将被广泛研究和优化的载体的两个成分是：1)衣壳，评估 基因转移的效率和稳定性，毒性，转基因和衣壳T细胞，预先存在的免疫和 生物分布；以及2)基因组，评估表达的峰值和开始。第二个具体目标是 分析预先存在的T细胞对甲型肝炎病毒衣壳病毒衣壳蛋白的作用 基因转移。第三个具体目标将评估目标器官在引出问题中的作用 免疫反应，特别集中于激活先天免疫或炎症。这些 研究将集中在建立小鼠系统的基本原则上，并选择性地在 非人灵长类动物。该项目将广泛使用向量和形态核心，并将合作 直接与项目II一起评估OTC缺陷小鼠模型中的媒介效果 通过提供用于分子表征的NHP组织。 版面描述。用于治疗非处方药缺乏的一种被称为临床候选的载体将是 已创建。将研究受体对载体的潜在免疫反应。

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.