Safe Focused Delivery of Gene Therapeutics to Colon

将基因治疗药物安全集中地输送到结肠

• 批准号: 6801877
• 负责人: TAKESHI SANO
• 金额: $ 25.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-19 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801877
• 关键词: Crohn' s disease; biotechnology; cell line; colon; enzyme linked immunosorbent assay; flow cytometry; gene delivery system; gene targeting; gene therapy; genetically modified animals; inflammatory bowel diseases; interleukin 10; laboratory mouse; technology /technique development; tissue /cell culture; transfection /expression vector; ulcerative colitis

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a safe, efficient gene transfer technology that can be used for gene therapy of diseases in the colorectal system. The R21 phase of this project will focus on the development of a gene transfer technology that allows safe, efficient, and focused delivery of transgenes to the colorectal system. During this technology development phase, we will use inflammatory bowel disease (IBD), which consists of Crohn's disease and ulcerative colitis, as a first target to assess the efficacy of the gene transfer technology. We have recently developed a novel gene transfer technology, in which viral particles (adenoviral vectors and adeno-associated viral vectors) are delivered to target sites in a microbead-associated form. These virus-microbead conjugates can infect target cells at efficiencies much greater than the same viral vectors used free in solution. A key feature of this gene transfer technology is that the infection sites by viral vectors are equal to the contact sites between target cells and virus-microbead conjugates. This allows focused delivery of transgenes to target sites with high transduction efficiencies by placing virus-microbead conjugates at the site of interest. Since each viral particle on the microbeads either mediates infection of a cell or stays on the microbeads, no free viral particles should be present. Thus, uncontrolled transduction of other non-target tissues or organs by viral vectors can be eliminated, and immune responses to viral vectors can be minimized. These and other characteristics suggest that this technology could allow for the efficient, safe delivery of transgenes to the colorectal system. In particular, it could be very useful for the development of effective gene therapy protocols for IBD, since a potentially efficacious gene therapy strategy for IBD is to repress intense inflammation in the colon by local, high-level expression of anti-inflammatory cytokines at inflamed lesions. We will investigate the potential of this gene transfer technology for the safe, focused delivery of the gene for a potent anti-inflammatory cytokine, interleukin-10 (IL-10), to inflamed lesions in the colon for the amelioration of established colitis. We hypothesize that this technology will allow for safe, efficient, and focused delivery of the IL-10 gene to inflamed lesions in the colon, resulting in the local expression and secretion of IL-10 in the inflamed lesions for the amelioration of established colitis with minimal detrimental effects on other tissues and organs.

描述(申请人提供)：该项目的长期目标是开发一种安全、高效的基因转移技术，可用于结直肠系统疾病的基因治疗。该项目的R21阶段将专注于开发一种基因转移技术，使转基因能够安全、高效和集中地输送到结直肠系统。在这一技术开发阶段，我们将使用由克罗恩病和溃疡性结肠炎组成的炎症性肠病(IBD)作为评估基因转移技术疗效的第一目标。我们最近开发了一种新的基因转移技术，在这种技术中，病毒颗粒(腺病毒载体和腺相关病毒载体)以微珠相关的形式输送到靶部位。这些病毒微珠结合物可以比在溶液中使用的相同病毒载体的效率高得多的效率感染目标细胞。这种基因转移技术的一个关键特点是病毒载体的感染部位等于靶细胞与病毒-微球结合物之间的接触部位。这使得通过在感兴趣的部位放置病毒-微珠结合物，以高转导效率将转基因集中输送到靶部位。由于微珠上的每个病毒颗粒要么介导细胞感染，要么停留在微珠上，因此不应该存在游离的病毒颗粒。因此，可以消除病毒载体对其他非靶组织或器官的不受控制的转导，并可以最大限度地减少对病毒载体的免疫反应。这些和其他特征表明，这项技术可以允许高效、安全地将转基因输送到结直肠系统。特别是，它可能对开发有效的IBD基因治疗方案非常有用，因为IBD的一个潜在有效的基因治疗策略是通过在炎症病变处局部高水平表达抗炎细胞因子来抑制结肠的强烈炎症。我们将研究这种基因转移技术的潜力，将一种有效的抗炎细胞因子白介素10(IL-10)的基因安全、集中地输送到结肠炎的结肠炎病变中，以改善已建立的结肠炎。我们推测，这项技术将允许将IL-10基因安全、有效和集中地传递到结肠的炎症病变，导致IL-10在炎症病变中的局部表达和分泌，从而在对其他组织和器官的损害最小的情况下改善已有的结肠炎。