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Improved Adenoviral Vectors for Hepatic Gene Therapy

用于肝脏基因治疗的改良腺病毒载体

基本信息

批准号：
7028393
负责人：
Mark A Kay
金额：
$ 31.43万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-30 至 2007-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Recombinant adenoviral vectors have had a stormy history. Nevertheless, there is promise in the development of gene-deleted adenoviruses because of reduced toxicity, efficient gene transfer, and large DNA carrying capacity. The goal of this project is to develop scientific principles required for production and evaluation of gene-deleted adenoviral vectors that remain episomal and/or integrate into host chromosomal DNA. The new vectors will be assessed in animals for efficacy as well as safety with the primary focus being on liver gene transfer. Using DNA transposons and site-specific phage integrases, we plan to develop gone-deleted vectors that can integrate an expression cassette into the host chromosome. Both episomal and integrating gene deleted vectors will be compared for longevity of therapeutic gene expression in a dog model of hemophilia. This will allow us to establish the utility of use of the vector for treating genetic diseases where life-long gene expression is required in most situations. We will begin to attempt to unravel the molecular state of the vector DNA and identify cellular proteins that may be involved in stabilizing episomal adenoviral vector DNAs in vivo. Taken together, these studies will advance our basic understanding of vector-host interactions related to persistence of vector in rive, as well as advancing therapeutic applications in preclinical development.

描述（由申请人提供）：重组腺病毒载体有一段风雨飘摇的历史。尽管如此，基因缺失的腺病毒的发展是有希望的，因为降低的毒性，有效的基因转移，和大的DNA携带能力。该项目的目标是制定生产和评估基因缺失的腺病毒载体所需的科学原则，这些载体保持游离型和/或整合到宿主染色体DNA中。将在动物中评估新载体的有效性和安全性，主要关注肝脏基因转移。利用DNA转座子和位点特异性噬菌体整合酶，我们计划开发gone缺失的载体，可以将表达盒整合到宿主染色体中。将比较附加型和整合基因缺失载体在血友病狗模型中治疗基因表达的寿命。这将使我们能够建立使用载体治疗遗传性疾病的效用，其中在大多数情况下需要终身基因表达。我们将开始尝试解开载体DNA的分子状态，并鉴定可能参与体内稳定附加型腺病毒载体DNA的细胞蛋白。总而言之，这些研究将促进我们对与载体在河中的持久性相关的载体-宿主相互作用的基本理解，并推进临床前开发中的治疗应用。