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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：
8795156
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8795156
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 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 Relative (related person)Resistance Retroviral Vector Safety Shuttle Vectors 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 integration site lentiviral integration leukemia mouse model novel promoter 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）：柏林一名白血病患者接受异基因造血干细胞移植后，HIV明显治愈的证明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。我们以前开发了泡沫病毒（FV）抗HIV载体，有效地抑制HIV复制，并有效地在小鼠异种移植模型中复制人类再生细胞。在这里，我们将开发改进的组合FV载体，旨在抑制HIV逃逸，并在准备使用FV载体在临床上更安全。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，并更好地了解潜在克隆扩增和原癌基因激活方面的安全性。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特征以及有效递送干扰基于HIV的慢病毒的抗HIV转基因的能力。载体滴度。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。我们还将探索通过修改整合模式以引导整合远离包括原癌基因在内的基因来使FV载体更安全的方法。我们将使用我们具有丰富经验的已建立异种移植模型，在人体再生细胞中评价体内安全性。我们的提案利用了FV载体的几个独特性质，并建立在我们已发表的数据基础上，这些数据表明FV载体有效地递送干扰基于HIV的慢病毒载体的抗HIV转基因。