Immune Responses To AAV-Mediated FIX Gene Transfer

AAV 介导的 FIX 基因转移的免疫反应

• 批准号: 7458702
• 负责人: Hildegund C. J. Ertl
• 金额: $ 161.89万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-05 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458702
• 关键词: Immune; Responses; AAV; Mediated; FIX

DESCRIPTION (provided by applicant): The goal of this application is to further characterize immune responses that can cause the elimination of recombinant adeno-associated virus (rAAV) transduced cells. Most humans are naturally exposed to AAV-2 together with a helper virus and thus have immunological memory to AAV-2. Memory T cells can be triggered more readily than naive lymphocytes, which was not taken into account by pre-clinical animal experiments conducted thus far. Concerns about immunological consequences of rAAV-mediated gene transfer were substantiated by the outcome of a clinical trial in which human hemophilia B patients were infused into the liver with rAAV-2-F.IX vectors. Only one patient achieved therapeutic levels of F.IX, which were sustained for 4 weeks and then started to decline. At the same time the patient developed a transaminitis, which resolved after F.IX levels decreased to baseline levels. Overall, the patient's clinical course was compatible with immune-mediated destruction of rAAV-transduced hepatocytes. Additional data generated since substantiated our hypothesis that AAV-2-specific T cells induced by a natural infection can cause elimination of rAAV-transduced hepatocytes. To further define immune responses to AAV and rAAV-encoded transgenes under conditions thai mimic those of human hemophilia patients and to then devise informed strategies to circumvent such problems we are proposing 4 interlinked Projects supported by 2 Cores. Project 1 will define T cell responses to AAV capsid proteins in humans and in non-human primates and assess their effect on hepatic rAAV-mediated gene transfer. Project 2 will elucidate the effect of pre-existing AAV-2-specific T cell-mediated immunity on hepatic rAAV vector-mediated gene transfer in mice. Project 3 will define regulatory immune responses that prevent induction of CD8+ T cell responses to a rAAV-encoded transgene product. Project 4 will focus on the potential use of regulatory T cells to ablate unwanted immune responses to rAAV-mediated gene transfer. The projects will be supported by an Administrative Core, which will provide the needed oversight, and a Vector Core, which will provide the investigators with purified and quality controlled vectors.

描述（由申请人提供）：本应用的目的是进一步表征可能导致重组腺相关病毒（RAAV）转导细胞的免疫反应。大多数人自然地与辅助病毒一起暴露于AAV-2，因此对AAV-2具有免疫记忆。与幼稚的淋巴细胞相比，记忆T细胞可以更容易触发，迄今为止进行的临床前动物实验尚未考虑到这一点。临床试验的结果证实了对RAAV介导的基因转移的免疫学后果的担忧，在该试验中，人类血友病患者用RAAV-2-F.IX载体注入肝脏中。只有一名患者达到了f.ix的治疗水平，该水平持续了4周，然后开始下降。同时，患者患有跨氨基炎，在F.IX水平降低到基线水平后，该炎后解决。总体而言，患者的临床过程与免疫介导的RAAV转移肝细胞的破坏兼容。产生的其他数据是因为我们证实了我们的假设，即自然感染诱导的AAV-2特异性T细胞会导致消除RAAV转移的肝细胞。为了进一步定义对AAV和RAAV编码的转基因的免疫反应，泰国模仿了人类血友病患者的免疫反应，然后制定了知情的策略来规避此类问题，我们提出了4个相互联系的项目，由2个核心支持。项目1将定义对人类和非人类灵长类动物中AAV CAPSID蛋白的T细胞反应，并评估其对肝RAAV介导的基因转移的影响。项目2将阐明预先存在的AAV-2特异性T细胞介导的免疫对小鼠肝介导介导的基因转移的影响。项目3将定义调节免疫反应，以防止CD8+ T细胞对RAAV编码的转基因产品的诱导。项目4将集中于调节性T细胞的潜在用途来消除对RAAV介导的基因转移的不良免疫反应。这些项目将得到行政核心的支持，该核心将提供所需的监督和向量核心，该核心将为调查人员提供纯净和质量控制的向量。