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的异基因造血干细胞移植后艾滋病毒明显治愈的证明为艾滋病基因治疗提供了重要的原则证据。然而，抗HIV基因的低效转移在艾滋病基因治疗临床试验中的成功是有限的。我们之前开发了泡沫病毒(FV)抗HIV载体，它可以有效地抑制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，我们将开发改进的组合FV载体，旨在抑制HIV逃逸，并为将FV载体应用于临床做准备。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，并从潜在的克隆扩张和原癌基因激活的角度更好地了解安全性。FV载体为艾滋病基因治疗提供了几个优点，包括独特的和潜在的更安全的整合模式，以及有效地传递干扰基于HIV的慢病毒的抗HIV转基因的能力 病媒滴度。我们将开发改进的、更安全的FV抗HIV载体，并直接将它们的安全性与目前正在临床试验中使用的慢病毒载体进行比较。我们还将探索使FV载体更安全的方法，方法是修改整合配置文件，以引导整合远离包括原癌基因在内的基因。我们将使用我们有丰富经验的已建立的异种移植模型在体内评估人类重新繁殖细胞的安全性。我们的建议利用了FV载体的几个独特特性，并建立在我们发表的数据的基础上，这些数据表明FV载体有效地传递干扰基于HIV的慢病毒载体的抗HIV转基因。

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.