Immune Responses to AAV-Mediated FIX Gene Transfer

本竞争性更新应用的总体主题是表征由腺相关病毒（AAV）载体介导的基因转移引起的免疫反应，并设计出规避阻碍持续基因转移的效应免疫反应的途径。在其1(r)'目标中，该项目将使用体外系统、实验动物和人类受试者样本，分析T细胞对不同血清型衣壳或转基因衣壳假型的AAV载体衣壳抗原的反应，以评估自然感染或AAV基因转移诱导的T细胞的功能，并确定T细胞对后者反应的寿命。途径，以规避破坏性T细胞反应的AAV基因转移，包括衣壳修饰和药物干预将被探索。该项目的目标是分析T细胞对AAV载体转基因产物的反应，重点关注双链AAV载体，根据该项目的初步数据，双链AAV载体比单链AAV载体能引发更强的先天和适应性免疫反应。在其目标中，该计划将探索使用调节性T细胞（Tregs）来抑制针对AAV衣壳或治疗性蛋白（如凝血因子）的破坏性免疫反应，以防止对基因转移的主要反应或下调对AAV介导的基因转移或蛋白质治疗的现有反应。该计划分为3个项目，由2个核心支持。

The overall theme of this competitive renewal application is to characterize immune responses induced upon gene transfer by adeno-associated virus (AAV) vectors and to devise avenues to circumvent effector Immune responses that impede sustained gene transfer. In its 1(r)' objective, the program will analyze T cell responses to the capsid antigens of AAV vectors pseudotyped with capsids of different serotypes or with genetically modified capsids using in vitro systems, experimental animals and samples from human subjects to assess functionality of T cells induced by natural infections or AAV gene transfer and to determine the longevity of T cell responses to the latter. Avenues to circumvent destructive T cell responses to AAV gene transfer including capsid modifications and pharmacological interventions will be explored. In its 2"" objective, the program will analyze T cell responses to the transgene product of AAV vectors with focus on double-stranded AAV vectors that according to preliminary data of the program elicit more potent innate and adaptive immune responses than single-stranded AAV vectors. In its 3"^ objective, the program will explore the use of regulatory T cells (Tregs) to suppress destructive immune responses against AAV capsid or therapeutic proteins such as clotting factors to prevent a primary response to gene transfer or to down-regulate an existing response to AAV-mediated gene transfer or protein therapy. The program is divided into 3 Projects supported by 2 Cores. Project 1 (KA High): Immune Responses to Capsid in AAV-Mediated Gene Transfer Project 2 (HC ErtI): T Cells to AAV and AAV-Encoded Transgene Products Project 3 (RW Herzog, C Terliorst): Pathways Towards Immune Tolerance to Coagulation Factors Core A (HC ErtI): Administrative Core Core B (S Zliou): Vector Core