Foamy Virus Vectors for Gene Therapy for HIV Infection

用于 HIV 感染基因治疗的泡沫病毒载体

• 批准号: 7082871
• 负责人: Jason A Taylor
• 金额: $ 11.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082871
• 关键词: CD34 molecule; HIV infections; Retroviridae; biotechnology; clinical research; cord blood; gene therapy; hematopoietic stem cells; human tissue; laboratory mouse; technology /technique development; transfection /expression vector; virus genetics; virus protein; virus replication

DESCRIPTION (provided by applicant): This proposal describes a five-year training program to develop an academic career in Hematology/Oncology and gene therapy. The program will further advance the investigator's research in the development of viral vector strategies for the treatment of HIV. The investigator will be mentored by Dr. David Russell, well recognized for his achievements in developing viral vector systems. The treatment of advanced HIV infection has been complicated by the continuing appearance of drug resistance strains. There are limited treatment options available to individuals infected with HIV resistant to multiple classes of drugs. Aggressive therapeutic options, including gene therapy, are appropriate for these individuals. A major limitation of clinical gene therapy trials has been poor gene transfer into hematopoietic stem cells (HSCs). Dr. Russell's laboratory has demonstrated efficient gene transfer rates into HSCs, using retroviral vectors based on foamy virus (FV). There are clear advantages for using FV vectors for gene therapy to treat HIV infection. These advantages include: 1) wild-type FV infection is non-pathogenic in all animal hosts, 2) FV vectors efficiently transduce human HSCs, and 3) unlike lentiviral vectors, FV vectors can target critical HIV proteins, such as Rev, without reduction in titer. The objectives of this proposal are to develop FV vectors containing anti-HIV gene strategies and to perform preclinical assessment of the vector's ability to transduce and protect differentiated human CD34 cells from wild-type HIV infection. The specific aims of the proposal include: 1) Create and test foamy viral vectors containing a transdominant inhibitor Rev protein; 2) Develop FV vectors that combine different strategies that block HIV; and 3) Add a drug selection element to the combination anti-HIV FV vectors and demonstrate in vivo selection in a murine model. The completion of this project and the training received at the University of Washington will prepare the principle investigator to be a leading researcher in gene therapy.

描述（由申请人提供）：该提案描述了一项为期五年的培训计划，以发展血液学/肿瘤学和基因疗法的学术生涯。该计划将进一步推进研究者在开发艾滋病毒治疗的病毒载体策略方面的研究。调查人员将由戴维·罗素（David Russell）博士指导，他在开发病毒媒介系统方面取得的成就而受到认可。 耐药性菌株的持续出现使晚期HIV感染的治疗变得复杂。感染了抗多种类药物的艾滋病毒的个体，可以使用有限的治疗选择。包括基因治疗在内的积极的治疗选择适合这些人。临床基因治疗试验的主要局限性是基因转移到造血干细胞（HSC）中。罗素博士的实验室已经使用基于泡沫病毒（FV）的逆转录病毒载体证明了有效的基因转移率。使用FV媒介来治疗HIV感染有明显的优势。这些优点包括：1）在所有动物宿主中，野生型FV感染均非致病性，2）FV载体有效地转导人类HSC，而3）与慢病毒载体不同，FV向量可以靶向关键的HIV HIV蛋白，例如不减少TITER中的REV，而无需降低。该提案的目标是开发含有抗HIV基因策略的FV矢量，并对媒介转导和保护分化的人CD34细胞免受野生型HIV感染的能力进行临床前评估。该提案的具体目的包括：1）创建和测试含有跨抑制剂REV蛋白的泡沫病毒载体； 2）开发FV向量结合了阻碍艾滋病毒的不同策略； 3）在组合抗HIV FV载体中添加药物选择元件，并在鼠模型中演示体内选择。 该项目的完成以及华盛顿大学接受的培训将使主要研究人员成为基因疗法的主要研究人员。