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 基因治疗的免疫障碍 通过使用自我互补基因组，新型 AAV 血清型的性能已得到极大改善。 改善了肝脏定向体内基因治疗成功的前景。尽管有这些令人鼓舞的数据， 仍然存在许多潜在障碍，主要集中在体内基因治疗的免疫生物学方面。 该项目将系统地解决新型 AAV 体内基因治疗的免疫反应作为 是临床应用中考虑的先决条件。第一个具体目标将侧重于识别 临床候选者的定义为第一阶段临床试验中要考虑的实际载体。这 将被广泛研究和优化的载体的两个组成部分是：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； 2) 基因组，评估表达峰值和起始时间。第二个具体目标是 分析预先存在的 T 细胞对 AAV 衣壳在肝脏定向治疗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 免疫反应，特别关注先天免疫或炎症的激活。这些 研究将集中在小鼠系统上，以建立基本原则，并有选择地遵循这些原则 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 Project II 合作评估 OTC 缺陷小鼠模型中的载体功效，并与 Project II 合作 III 通过提供 NHP 组织进行分子表征。 平铺说明。用于治疗 OTC 缺乏症的载体（称为临床候选药物）将是 创建的。将研究接受者对载体的潜在免疫反应。