LENTIVIRUS-BASED IMMUNOTHERAPY FOR AIDS

描述(由申请人提供)：该提案阐述了使用慢病毒载体介导的抗HIV RNA干扰(RNAi)策略的T细胞免疫疗法的发展。评估RNAi对转导的T细胞或从干细胞分化为T细胞的任何功能效应将是该提案的一个重要目标。因此，该计划将重点放在T细胞模型上，用于评估针对HIV的增强型RNAi改良慢病毒载体的安全性，并将包括一项评估慢病毒转导T细胞免疫疗法安全性的I期临床研究。此外，动物模型的临床前研究将解决与艾滋病干细胞来源的T细胞恢复相关的重要问题，特别是如何进行有效的非清髓性自体干细胞移植，如何选择转导细胞，以及这种方法在这些模型中是否提供了对HIV或SIV的保护。由学术和私营部门的研究人员组成的联盟在RNAi、T细胞扩增、检测转导细胞中的siRNA、SCID-Hu模型和非人类灵长类动物移植模型以及基于细胞的基因转移研究方面拥有卓越的研究能力。最后，在小动物和大动物模型中从慢病毒载体转导的干细胞中选择T细胞的方法的发展将为最终在艾滋病中基于干细胞的免疫重建提供重要信息。 项目1：在BRICOH，J Rossi和CSU(R.Akina)和Benitec Australia Ltd.(K.Reed)的合作者将专注于开发艾滋病毒的优化RNAi抑制，并将使用SCID-HU模型来预测总体临床结果。 项目2：在BRICOH，J.K.Yee和CSU(R.Akina)的合作者将开发改进的慢病毒载体，并研究慢病毒载体介导的RNAi转导和细胞选择后T细胞的功能。 项目3：在FHCRC和华盛顿大学，H-P Kiem和他的同事将在猕猴模型中开发慢病毒载体修饰干细胞移植和选择的概念测试，并进行SIV挑战。 项目4：在BRICOH，J.Zaia和他的同事，以及在宾夕法尼亚大学(C.六月)，将使用CD4细胞免疫疗法对慢病毒/RNAi安全性进行I阶段评估。该计划得到三个核心的支持：BRICOH的行政中心(核心A)、BRICOH的抗病毒实验室(核心B)以及国际治疗公司和BRICOH的临床资源中心(核心C)。

DESCRIPTION (provided by applicant): The proposal addresses the development of T-cell immunotherapy using lentiviral -vector mediated anti-HIV RNA interence (RNAi) strategies. The assessment of any functional effect of RNAi on transduced T-cells or on the differentiation ofT-cells from stem cells will be an important goal of this proposal. Thus, the program will focus on T-cell models for evaluation of the safety of improved lentivims vectors with enhanced RNAi targeted to HIV, and will include a phase I clinical study evaluating the safety of lentivirus transduced T-cell immunotherapy. In addition, preclinieal research in animal models will address important questions relevant to stem cell-derived T-cell restoration in AIDS, especially how to perform efficient non-myeloablative autologous stem cell transplantation, how to select for transduced cells, and whether this approach provides protection from HIV or SHIV in these models. The consortium of academic and private sector investigators have exceptional research abilities in RNAi, in T-cell expansion, in detection of siRNA in transduced cells, in the SCID-hu model and the nonhuman primate transplantation model, and in cell-based gene transfer research. Finally, the development of a method for selection of T-cells from lentiviral vector-transduced stem cells in small animal and large animal models will provide the important information leading to eventual stem cellbased immune reconstitution in AIDS. Project 1: At BRICOH, J Rossi and collaborators at CSU (R. Akkina) and at Benitec Australia Ltd. (K. Reed) will focus on the development of optimized RNAi inhibition of HIV and will use a SCID-hu model to predict the overall clinical outcomes. Project 2: At BRICOH, J. K. Yee and collaborators at CSU (R. Akkina) will develop improved lentivirus vectors and study the function of T-cells after lentiviral vector mediated RNAi transduction and cell selection. Project 3: At FHCRC and the UW, H-P Kiem and colleagues will develop a test-of-concept of lentiviral vector modified stem cells transplantation and selection, with SHIV challenge, in a macaque model. Project 4: At BRICOH, J. Zaia and colleagues, and at UPENN (C. June) will conduct a phase I evaluation of lentivirus/RNAi safety using CD4-cell immunotherapy. The program is supported by 3 cores: the Administration Center (Core A) at BRICOH, the Antiviral Laboratory (Core B) at BRICOH, and the Clinical Resource Center (Core C) at International Therapeutics Inc. and at BRICOH.