Engineering Improved Retroviral Stability

工程改进逆转录病毒稳定性

• 批准号: 0828244
• 负责人: Martin Yarmush
• 金额: $ 28.04万
• 依托单位: Rutgers University New Brunswick
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0828244&HistoricalAwards=false
• 关键词: Engineering; Improved; Retroviral; Stability

CBET-0828244M. Yarmush, Rutgers University New BrunswickThe overall goal of the proposed research is to develop effective strategies to increase the stability and titer of retroviral vectors for gene therapy applications. Recently, considerable effort has been dedicated toward utilizing these, and other viral, vectors in a number of clinical trials. Although several publications have described various degrees of success, the clinical success of retroviral vectors is limited by the rapid rate of viral inactivation and limited viral titers. Thus, a retrovirus with enhanced intrinsic stability and high titer would alleviate some of the practical obstacles limiting the success of retroviral vectors in the clinic. It is likely that these principles could also be extended to other viral vectors. The proposed research seeks to accomplish the following: (1) To determine the mechanisms underlying the loss of retroviral bioactivity and the relative stability of the immature / mature viral particles; (2) To optimize culture conditions and methods, in order to allow the production of high-titer viral vectors; and (3) To modify the viral reverse transcriptase to achieve higher efficiency viral replication. To achieve these goals, physical, chemical, and molecular manipulation techniques will be used with the objective of slowing the rate of retroviral decay and increasing retroviral titer. The proposed work will provide excellent training for the graduate fellows involved in the project, as well as to students exposed to it through various courses and training programs conducted by the investigators. In addition, the PI will provide an excellent educational environment for various high school and university-wide undergraduate research programs. The scientific approach was designed not only to establish an excellent scientific program, but also to expose students to state of the art technology and methodology through both classroom instruction and direct laboratory interaction. The research itself will provide valuable new information regarding the mechanisms of retroviral decay and methods to address them. The experimental results are likely to have a broad impact on the scientific and clinical venues which utilize or are developing viral vector delivery protocols. In summary, the proposed work seeks to provide fundamental research and a human base of personnel equipped to solve problems related to the implementation of techniques to improve suitability of viral vectors for gene therapy applications.

CBET-0828244M。Yarmush，Rutgers University New Brunswick拟议研究的总体目标是开发有效的策略，以增加用于基因治疗应用的逆转录病毒载体的稳定性和滴度。最近，相当大的努力已经致力于在许多临床试验中利用这些和其他病毒载体。尽管一些出版物已经描述了不同程度的成功，但逆转录病毒载体的临床成功受到病毒灭活速度快和病毒滴度有限的限制。因此，具有增强的内在稳定性和高滴度的逆转录病毒将减轻限制逆转录病毒载体在临床中成功的一些实际障碍。这些原则也可能扩展到其他病毒载体。拟开展的研究旨在实现以下目标：（1）确定逆转录病毒生物活性丧失和未成熟/成熟病毒颗粒相对稳定性的机制;（2）优化培养条件和方法，以生产高滴度病毒载体;（3）修饰病毒逆转录酶，以实现更高效的病毒复制。为了实现这些目标，将使用物理、化学和分子操作技术，目的是减缓逆转录病毒衰变的速度和增加逆转录病毒滴度。拟议的工作将为参与该项目的研究生研究员以及通过调查人员举办的各种课程和培训方案接触到该项目的学生提供出色的培训。此外，PI将为各种高中和大学本科研究项目提供良好的教育环境。 科学方法的目的不仅是建立一个优秀的科学计划，而且还通过课堂教学和直接的实验室互动，让学生接触到最先进的技术和方法。这项研究本身将提供有关逆转录病毒衰变机制和解决方法的宝贵新信息。实验结果可能对利用或正在开发病毒载体递送方案的科学和临床场所产生广泛影响。总之，拟议的工作旨在提供基础研究和人员配备，以解决有关的技术，以提高基因治疗应用的病毒载体的适用性的实施问题的人力基础。