Transposon Mediated Gene Therapy for Colorectal Cancer

转座子介导的结直肠癌基因治疗

• 批准号: 8053301
• 负责人: R. Scott McIvor
• 金额: $ 29.09万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-29 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053301
• 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

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）：结直肠癌是全球癌症死亡的主要原因之一，肝脏是结直肠癌转移发展的最常见和关键部位。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，不到10%的肝转移患者是合适的手术候选人，大多数患者在诊断为这种播散性疾病后2年内死亡。目前治疗方法的改进不太可能显著影响疾病的自然进展。结肠直肠癌的基因治疗是一种治疗选择，可以提供一种侵入性较小的疾病治疗。在这里，我们建议使用睡美人（SB）转座子载体系统，以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，将组装含有在肿瘤特异性启动子的转录调控下的抗血管生成和免疫刺激基因的睡美人转座子，并测试其体外基因表达和转座。在目标2中，使用Fractalkine受体肽两亲物，装载有报告基因和抗肿瘤治疗性转座子的隐形脂质体复合物将靶向肿瘤细胞。将测试这些复合物的体外抗肿瘤有效性。在目标3中，将报告转座子与或不与SB转座酶一起静脉内注射到荷瘤小鼠中，随后测试肿瘤中的持续基因表达。在目的4中，将治疗性转座子沿着SB转座酶编码质粒静脉内注射到荷瘤小鼠中。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，随后将开发通过非病毒基因疗法治疗转移性结直肠癌的临床试验。