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

基本信息

批准号：
8620606
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
项目类别：
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/8620606
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 Data Disease Gagging Gene-Modified Generations Genes Genome Goals HIV HIV Infections HIV-1 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 Relative (related person)Resistance Retroviral Vector Safety Shuttle Vectors Site Spumavirus System Therapeutic Transgenes Transplantation Viral Virus Integration Xenograft Model base cofactor combat combinatorial comparative efficacy deep sequencing design experience gene therapy gene therapy clinical trial genotoxicity improved in vivo lentiviral integration leukemia mouse model novel promoter public health relevance research study success transgene expression vector

项目摘要

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）：在柏林白血病患者的同种异体造血干细胞移植后，艾滋病毒的明显治愈方法的证明提供了重要的艾滋病基因治疗原则证明。但是，抗HIV基因的效率低下在艾滋病基因治疗临床试验中的成功有限。我们以前开发了泡沫病毒（FV）抗HIV载体，这些抗HIV载体有效抑制HIV复制并有效地转导人类自然移植模型中的人类再植物细胞。在这里，我们将开发改进的组合FV载体，旨在抑制HIV逃生，并为在诊所使用FV载体做准备更安全。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）开发有效抑制艾滋病毒复制和逃生的转基因组合，以及2）提高HSC基因治疗的安全性，并更好地了解潜在的克隆扩张和原始基因的激活方面的安全性。 FV矢量为AIDS基因疗法提供了几种优势向量滴度。我们将开发改进的，更安全的FV抗HIV载体，并将其安全性直接与目前用于临床试验中使用的慢病毒载体进行比较。我们还将通过修改整合曲线以直接远离包括原始基因在内的基因来探索使FV向量更安全的方法。我们将使用拥有丰富经验的已建立异种移植模型来评估人体重新流体细胞中的安全性。我们的建议利用了FV载体的几种独特属性，并基于我们已发布的数据，显示FV向量有效地提供了干扰基于HIV的慢病毒载体的抗HIV转基因。