Immune Barriers to AAV Gene Therapy

项目I -AAV基因治疗的免疫屏障 使用自我互补基因组的新型AAV血清型的性能极大地提高了AAV的免疫原性。 改善了成功的肝脏定向体内基因治疗的前景。尽管这些数据令人鼓舞， 许多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。 该项目将系统地解决新的AAV的体内基因治疗的免疫应答， 这是他们在临床应用中考虑的先决条件。第一个具体目标将侧重于确定 临床候选药物，定义为I期临床试验中考虑的实际载体。的 将被广泛研究和优化的载体的两个组成部分是：1）衣壳，评价 基因转移的效率和稳定性、毒性、转基因和衣壳T细胞、预先存在的免疫力和 生物分布;和2）基因组，评估表达的峰值和开始。第二个具体目标将 分析预先存在的T细胞对AAV衣壳在肝定向免疫的安全性和有效性方面的作用。 基因转移第三个具体目标将评估靶器官在引发问题中的作用。 免疫应答，特别是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则的鼠系统，这些原则将有选择地在 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 直接与项目II合作评估OTC缺陷小鼠模型中的载体效力，并与项目II合作评估 III通过提供NHP组织进行分子表征。 Lay描述。用于治疗OTC缺乏症的载体称为临床候选载体， 创造将研究受体对载体的潜在免疫应答。

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.