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Targeted adenovirus vectors for systemic application

用于全身应用的靶向腺病毒载体

基本信息

批准号：
7020731
负责人：
Dmitry Shayakhmetov
金额：
$ 18.5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2008-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Adenovirus vectors (Ad) are the second largest group of viral vectors that are extensively used in clinical trials in the US. The interest in Ad has recently expanded due to its potential as a vector for vaccination against anthrax and other life threatening infection agents. Despite significant knowledge regarding Ad interactions with cells in vitro, the molecular mechanisms governing infectivity, biodistribution and toxicity of systemically applied Ad vectors remain poorly understood. We hypothesize that the prevention of liver-mediated Ad clearance from the blood should allow for the improvement of Ad persistence in the circulation upon systemic vector application. We also hypothesized that combining in one vector the beneficial capsid modifications, which provide both vector targeting and stability in the blood, represents a feasible approach for the development of novel safe and effective therapeutics based on Ad. Recently we discovered a novel coagulation factor IX/blood factor-dependent pathway, responsible for the trapping of adenovirus vector by hepatocytes and Kupffer cells in vivo. This discovery represents a basis for the current proposal with the following specific aims: 1. Identify amino acid residues within Ad5 and Ad35 fiber knob domains responsible for binding to FIX. 2. Develop Ad5-based vectors possessing Ad5 and/or Ad35 fibers ablated for their binding to FIX and analyze their bio-distribution and persistence in circulation in a mouse model. 3. Analyze efficiency of target cell transduction by lung carcinoma cell-targeted, FIX binding-ablated Ad, upon its systemic application in a mouse model. These studies will dramatically improve our understanding of the mechanisms of Ad-host interactions in vivo and may ultimately lead to the development of safe and efficient Ad vectors for the therapy of a wide range of inborn and acquired human diseases.

描述（由申请人提供）：腺病毒载体（Ad）是第二大组病毒载体，广泛用于美国的临床试验。最近，人们对 Ad 的兴趣有所增加，因为它具有作为炭疽和其他危及生命的感染病原体疫苗接种载体的潜力。尽管人们对 Ad 与细胞的体外相互作用有大量了解，但对系统应用的 Ad 载体的感染性、生物分布和毒性的分子机制仍知之甚少。我们假设，预防肝脏介导的 Ad 从血液中清除应该可以改善全身载体应用后循环中 Ad 的持久性。我们还假设，将有益的衣壳修饰结合在一个载体中，提供载体靶向性和血液稳定性，代表了开发基于 Ad 的新型安全有效疗法的可行方法。最近，我们发现了一种新的凝血因子 IX/血液因子依赖性途径，负责体内肝细胞和库普弗细胞捕获腺病毒载体。这一发现代表了当前提案的基础，其具体目标如下： 1. 鉴定 Ad5 和 Ad35 纤维旋钮结构域内负责与 FIX 结合的氨基酸残基。 2. 开发基于 Ad5 的载体，该载体具有因与 FIX 结合而被烧蚀的 Ad5 和/或 Ad35 纤维，并分析它们在小鼠模型中的生物分布和循环持久性。 3. 分析肺癌细胞靶向、FIX 结合消除的 Ad 在小鼠模型中的全身应用后的靶细胞转导效率。这些研究将极大地提高我们对体内Ad-宿主相互作用机制的理解，并可能最终导致开发出安全有效的Ad载体，用于治疗各种先天性和后天性人类疾病。