Transposon Mediated Gene Therapy for Colorectal Cancer

转座子介导的结直肠癌基因治疗

基本信息

批准号：
7802899
负责人：
R. Scott McIvor
金额：
$ 30.14万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-29 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7802899
关键词：
Angiogenesis Inhibitors Angiostatins Animal Model Biological Assay Biological Models Cancer Cell Growth Cancer Etiology Cell Line Cells Cessation of life Chromosomes Clinical Treatment Clinical Trials Colon Carcinoma Colorectal Cancer Complex Development Diagnosis Disease Disease Progression Disseminated Malignant Neoplasm Drug Formulations Effectiveness Endostatins Ensure Excision Gene Delivery Gene Expression Gene Transfer Genes Immune Immune system In Vitro Inflammatory Response Link Liposomes Liver Liver neoplasms Lung Malignant Neoplasms Mediating Metastatic Neoplasm to the Liver Metastatic to Methods Modeling Modification Monitor Mus Neoplasm Metastasis Non-Viral Vector Oncogenes Operative Surgical Procedures Patients Peptides Plasmids Procedures Recurrence Reporter Reporter Genes Site Sleeping Beauty Staging Symptoms System Testing Therapeutic Time Toxic effect Transcriptional Regulation Transfection Transgenes Transposase Viral Viral Vector angiogenesis cancer cell clinically relevant fighting fractalkine receptor gene replacement gene therapy human disease in vitro testing in vivo metastatic colorectal mouse model neoplastic cell non-viral gene delivery non-viral gene therapy novel novel therapeutics outcome forecast preclinical study prevent promoter research study success therapeutic gene therapeutic transgene therapeutic transposons transgene expression tumor tumor growth uptake vector

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is one of the leading causes of cancer death worldwide, with the liver being the most common and critical site for development of colorectal cancer metastases. Current treatments include surgical resection, a highly invasive procedure. However, less than 10% of patients with liver metastases are appropriate surgical candidates and most patients die within 2 years of being diagnosed with such disseminated disease. Modifications of current treatments are unlikely to significantly influence the natural progression of the disease. Genetic therapy for colorectal cancer is a therapeutic alternative that could provide a less invasive treatment of the disease. Here, we propose to use the Sleeping Beauty (SB) transposon vector system, to provide sustained expression of the transgene, "which is required to halt tumor growth and prevent recurrence of metastatic cancer cell growth. Four specific aims are proposed. In Aim 1, Sleeping Beauty transposons containing antiangiogenic and immunostimulatory genes under transcriptional regulation of tumor specific promoters will be assembled and tested for gene expression and transposition in vitro. In Aim 2, stealth liposome complexes loaded with reporter and antitumor therapeutic transposons will be targeted to tumor cells using a fractalkine receptor peptide amphiphile. These complexes will be tested for their antitumor effectiveness in vitro. In Aim 3, reporter transposons will be injected intravenously with or without SB transposase into tumor bearing mice, subsequently testing for sustained gene expression in tumor. In Aim 4, therapeutic transposons along with SB transposase-encoding plasmid will be injected intravenously into tumor bearing mice. Antiangiogenic and immunostimulatory gene expression, duration of expression and inhibitory or suppressive effects on tumor growth will be monitored. These experiments will provide a clinically relevant model for targeted cancer gene therapy. Successful completion of these studies will set the stage for large animal model studies with subsequent development of a clinical trial for treatment of metastatic colorectal cancer by non-viral gene therapy.

描述（由申请人提供）：结直肠癌是全世界癌症死亡的主要原因之一，肝脏是结直肠癌转移最常见和最关键的部位。目前的治疗方法包括手术切除，这是一种高度侵入性的手术。然而，只有不到 10% 的肝转移患者适合手术治疗，大多数患者在被诊断患有这种播散性疾病后 2 年内死亡。对当前治疗方法的修改不太可能显着影响疾病的自然进展。结直肠癌的基因疗法是一种治疗替代方案，可以提供一种侵入性较小的疾病治疗方法。在这里，我们建议使用睡美人 (SB) 转座子载体系统来提供转基因的持续表达，“这是阻止肿瘤生长和防止转移性癌细胞生长复发所必需的。”提出了四个具体目标。在目标 1 中在目标 2 中，将组装含有受肿瘤特异性启动子转录调控的抗血管生成和免疫刺激基因的睡美人转座子，并在体外测试基因表达和转座。治疗性转座子将使用 fractalkine 受体肽两亲物靶向肿瘤细胞，这些复合物将在体外测试其抗肿瘤效果。在目标 3 中，报告转座子将在有或没有 SB 转座酶的情况下静脉注射到荷瘤小鼠体内，随后进行测试。在目标 4 中，治疗性转座子连同 SB 转座酶编码质粒将被静脉注射到荷瘤小鼠中。将监测抗血管生成和免疫刺激基因表达、表达持续时间以及对肿瘤生长的抑制或抑制作用。这些实验将为靶向癌症基因治疗提供临床相关模型。这些研究的成功完成将为大型动物模型研究奠定基础，随后开展非病毒基因疗法治疗转移性结直肠癌的临床试验。