Improved Foamy Virus Vectors for AIDS Gene Therapy

描述（由申请人提供）：柏林一名白血病患者异体造血干细胞移植后明显治愈HIV的演示为艾滋病基因治疗提供了重要的原理证明。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，它能有效地抑制HIV复制，并在小鼠异种移植模型中有效地转导人类再生细胞。在这里，我们将开发改进的FV组合载体，旨在抑制HIV逃逸，并为临床使用FV载体做准备。我们的建议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HIV复制和逃逸的转基因组合，2)提高HSC基因治疗的安全性，更好地了解原癌基因潜在克隆扩增和激活的安全性。FV载体为艾滋病基因治疗提供了几个优势，包括一种独特的、潜在更安全的整合谱，以及有效递送干扰基于hiv的慢病毒的抗hiv转基因的能力

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.