Improved Foamy Virus Vectors for AIDS Gene Therapy

用于艾滋病基因治疗的改进泡沫病毒载体

• 批准号: 8996672
• 负责人: GRANT D TROBRIDGE
• 金额: $ 37.1万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996672
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adoption; Affect; Allogenic; Autologous; Berlin; Biological Assay; CCR5 gene; CD34 gene; Cells; Clinic; Clinical; Clinical Trials; Clonal Expansion; DNA cassette; Data; Disease; Gene-Modified; Generations; Genes; Genome; Goals; HIV; HIV Infections; HIV-1; Health; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterochromatin; Homologous Protein; Housekeeping; Human; In Vitro; Integrase; Lead; Lentivirus Vector; Location; Methods; Modeling; Mus; Patients; Plasmid Cloning Vector; Plasmids; Preparation; Production; Property; Proteins; Proto-Oncogenes; Publishing; Resistance; Retroviral Vector; Safety; Shuttle Vectors; Spumavirus; System; Therapeutic; Transgenes; Transplantation; Viral; Virus Integration; Virus Replication; Xenograft Model; base; cofactor; combat; combinatorial; comparative efficacy; deep sequencing; design; experience; gene therapy; gene therapy clinical trial; genotoxicity; improved; in vivo; integration site; lentiviral integration; leukemia; mouse model; novel; promoter; research study; success; transgene expression; vector

DESCRIPTION (provided by applicant): The demonstration of an apparent cure for HIV after allogeneic hematopoietic stem cell transplantation of a leukemia patient in Berlin offers an important proof-of-principle for AIDS gene therapy. However, inefficient transfer of anti-HIV genes has limited success in AIDS gene therapy clinical trials. We previously developed foamy virus (FV) anti-HIV vectors that potently inhibit HIV replication and efficiently transduce human repopulating cells in a mouse xenotransplant model. Here we will develop improved combinatorial FV vectors designed to inhibit HIV escape and to be safer in preparation for using FV vectors in the clinic. Our proposal directly address two critical challenges for AIDS gene therapy, 1) to develop combinations of transgenes that potently inhibit HIV replication and escape, and 2) to improve the safety of HSC gene therapy and better understand safety in terms of potential clonal expansion and activation of proto-oncogenes. FV vectors offer several advantages for AIDS gene therapy including a distinct and potentially safer integration profile and the ability to efficiently deliver anti-HIV transgenes that interfere with HIV-based lentiviral vector titers. We will develop improved, safer FV anti-HIV vectors and directly compare their safety to lentiviral vectors which are currently being used in clinical trials. We will also explor ways to make FV vectors safer by modifying the integration profile to direct integration away from genes including proto-oncogenes. We will evaluate safety in vivo in human repopulating cells using an established xenograft model we have extensive experience with. Our proposal takes advantage of several unique properties of FV vectors and builds upon our published data showing FV vectors effectively deliver anti-HIV transgenes that interfere with HIV-based lentiviral vectors.

描述（由申请人提供）：在柏林对一名白血病患者进行同种异体造血干细胞移植后，艾滋病毒明显治愈，这为艾滋病基因治疗提供了重要的原理验证。然而，抗HIV基因的低效转移限制了艾滋病基因治疗临床试验的成功。我们之前开发了泡沫病毒 (FV) 抗 HIV 载体，可有效抑制 HIV 复制并在小鼠异种移植模型中有效转导人类再生细胞。在这里，我们将开发改进的组合 FV 载体，旨在抑制 HIV 逃逸，并为在临床中使用 FV 载体做好准备。我们的提案直接解决了艾滋病基因治疗的两个关键挑战，1）开发有效抑制艾滋病毒复制和逃逸的转基因组合，2）提高HSC基因治疗的安全性，并更好地了解原癌基因潜在克隆扩张和激活方面的安全性。 FV 载体为艾滋病基因治疗提供了多种优势，包括独特且可能更安全的整合特性，以及有效传递干扰基于 HIV 的慢病毒的抗 HIV 转基因的能力 向量滴度。我们将开发改进的、更安全的FV抗HIV载体，并直接将其安全性与目前用于临床试验的慢病毒载体进行比较。我们还将探索如何通过修改整合配置文件以直接整合远离包括原癌基因在内的基因，从而使 FV 载体更安全。我们将使用我们拥有丰富经验的已建立的异种移植模型来评估人类再生细胞的体内安全性。我们的提案利用了 FV 载体的几个独特特性，并以我们已发表的数据为基础，这些数据显示 FV 载体有效地传递抗 HIV 转基因，干扰基于 HIV 的慢病毒载体。