Safe Focused Delivery of Gene Therapeutics to Colon

项目描述（申请人提供）：本项目的长期目标是开发一种安全、有效的基因转移技术，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，该技术可以安全，有效和集中地将转基因传递到结直肠系统。 在此技术开发阶段，我们将使用炎症性肠病（IBD），其中包括克罗恩病和溃疡性结肠炎，作为评估基因转移技术疗效的第一个目标。 我们最近开发了一种新的基因转移技术，其中病毒颗粒（腺病毒载体和腺相关病毒载体）以微珠相关的形式被递送到靶位点。 这些病毒-微珠缀合物可以以比在溶液中游离使用的相同病毒载体高得多的效率感染靶细胞。 这种基因转移技术的一个关键特征是病毒载体的感染位点等于靶细胞与病毒-微珠缀合物之间的接触位点。 这允许通过将病毒-微珠缀合物放置在感兴趣的位点，以高转导效率将转基因集中递送到靶位点。 由于微珠上的每个病毒颗粒介导细胞的感染或停留在微珠上，因此不应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，并且可以最小化对病毒载体的免疫应答。 这些和其他特征表明，这项技术可以允许有效，安全地将转基因传递到结直肠系统。 特别是，它可能是非常有用的IBD的有效的基因治疗方案的发展，因为IBD的一个潜在的有效的基因治疗策略是抑制强烈的炎症在结肠局部，高水平表达的抗炎细胞因子在发炎的病变。 我们将研究这种基因转移技术的潜力，安全，集中交付的基因的一种有效的抗炎细胞因子，白细胞介素-10（IL-10），在结肠炎性病变的改善建立结肠炎。 我们假设该技术将允许IL-10基因安全、有效和集中地递送至结肠中的发炎病变，导致IL-10在发炎病变中的局部表达和分泌，用于改善已建立的结肠炎，对其他组织和器官的有害影响最小。

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.