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EPISOMAL VECTORS FOR COLON CANCER GENE THERAPY

EPISOMAL VECTORS FOR COLON CANCER GENE THERAPY
结肠癌基因治疗的特殊载体
批准号:
6137584
负责人:
MARK J COOPER
金额:
$13.59万
依托单位国家:
美国
项目类别:
财政年份:
1997
资助国家:
美国
项目状态:
已结题
起止时间:
1997-01-20 至 2000-12-31

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中文摘要
翻译
描述:(申请人摘要)申请人的实验室最近 构建一种基于SV40的新型人类基因外体表达载体 预计在允许高复制率的情况下安全的治疗应用 在人类细胞中复制。该上体质粒利用一种特定的 设计SV40大T抗原突变体驱动染色体外复制 在人类细胞中,同时消除大T抗原不受欢迎的能力 结合和失活宿主P53和Rb抑癌基因蛋白。因为 该载体在基因表达后2-3天内可复制数千个拷贝 转移后,预计表达系统将安全地表达目的基因 每个细胞的水平比目前发表的任何基因治疗载体都要高。 进一步修改此载体以包括适当的安全性和 复制控制元件,申请人提议开发一种新的 “结肠癌特异性”表达系统将被放大 并仅在肿瘤细胞中表达靶基因。特定的 目标1是开发一种非传染性的、安全修改的SV40为基础的上体 允许肿瘤特异性载体的外部控制的表达系统 扩增和基因表达。一个基于SV40的异构体表达系统 将构建同时使用组织特异性和诱导性的 限制突变T抗原表达的启动子,因此载体 扩增,对结肠肿瘤细胞。具体目标2是确定 基于SV40的疱疹病毒编码载体系统的有效性研究 单纯疱疹病毒胸苷激酶体外杀伤肿瘤细胞。曝光后 对于GCV,将评估肿瘤细胞杀伤的特异性和有效性。 在特定的目标3中,将使用临床前结肠癌模型来 评价基于SV40的内切体清除已建立的肿瘤的能力 脂质体介导的裸鼠异种移植瘤研究。老鼠会成为 随访观察肿瘤消退情况和生存情况。总而言之,这个应用程序 支持关键的、初步的“原则证明”实验,以评估 用于基因治疗的“肿瘤特异性”附体载体和基因转移系统 结肠癌。
英文摘要
DESCRIPTION: (Applicant's Abstract) The applicant's laboratory has recently developed a novel SV40-based episomal expression vector for human gene therapy applications that is predicted to be safe while permitting high copy replication in human cells. This episomal plasmid utilizes a specifically designed SV40 large T antigen mutant to drive extrachromosomal replication in human cells while eliminating the undesired ability of large T antigen to bind and inactivate host p53 and RB tumor suppressor gene proteins. Because this vector replicates to thousands of copies by 2-3 days after gene transfer, the expression system is predicted to safely express target genes at higher levels per cell than any currently published gene therapy vector. To further modify this vector to include appropriate safety and replication-control elements, the applicant proposes to develop a novel "colon cancer-specific" expression system which will amplify extrachromosomally and express target genes only in tumor cells. Specific Aim 1 is to develop a noninfectious, safety-modified SV40 based episomal expression system to permit external control of tumor-specific vector amplification and gene expression. An SV40-based episomal expression system will be constructed which employs both tissue-specific and inducible promoters to limit expression of mutant T antigen, and hence vector amplification, to colon tumor cells. Specific Aim 2 is to determine the effectiveness of the SV40-based episomal vector system encoding herpes simplex virus thymidine kinase to kill tumor cells in vitro. After exposure to GCV, the specificity and efficiency of tumor cell kill will be evaluated. In Specific Aim 3 a preclinical colon cancer model will be employed to evaluate the ability of SV40-based episomes to eradicate established tumor xenografts in nude mice using liposome-mediated gene transfer. Mice will be followed for tumor regression and survival. In summary, this application supports key, initial "proof-of-principle" experiments to evaluate "tumor-specific" episomal vectors and gene transfer systems for gene therapy of colon cancer.
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Intrapulmonary Gene Transfer Using Compacted DNA
  • 批准号:
    6401494
  • 项目类别:
  • 资助金额:
    $10.0万
  • 财政年份:
    2001
  • 负责人:
    MARK J COOPER
  • 依托单位:
VACCINATION BY TOPICAL APPLICATION OF CONDENSED DNA
  • 批准号:
    6211596
  • 项目类别:
  • 资助金额:
    $10.0万
  • 财政年份:
    2000
  • 负责人:
    MARK J COOPER
  • 依托单位:
EPISOMAL VECTORS FOR BREAST CANCER GENE THERAPY
  • 批准号:
    6210668
  • 项目类别:
  • 资助金额:
    $9.95万
  • 财政年份:
    2000
  • 负责人:
    MARK J COOPER
  • 依托单位:
EPISOMAL VECTORS FOR COLON CANCER GENE THERAPY
  • 批准号:
    2633947
  • 项目类别:
  • 资助金额:
    $4.9万
  • 财政年份:
    1997
  • 负责人:
    MARK J COOPER
  • 依托单位:
海外基金