IL-1 RECEPTOR ANTAGONIST GENE THERAPY FOR THE TREATMENT OF INFLAMMATORY DISEASES

我们的实验室已经证明用重组IL-1治疗 反复注射受体拮抗剂(IL-1ra)显著抑制 实验性结肠炎的炎症和组织损伤。此外，我们 最近有研究表明，溃疡性结肠炎和克罗恩病患者 疾病患者肠道IL-1ra/IL-1比值较正常降低 对照和自限性感染性结肠炎，提示患者 患有炎症性肠病的人可能有能力缺陷 产生IL-1ra。因此，恢复生理平衡 IL-1ra和IL-1之间可能被证明有益于减少肠道 发炎。我们的假设是，细胞的发育 一种能稳定生产和运送重组人的移植系统 IL-1ra进入体循环可能代表着一个重要的进展 我们治疗炎症性疾病的能力，包括炎症性疾病 已证明IL-1在其中起作用的肠道疾病和肝脏疾病 一个重要的角色。这一假设将通过完成 具体目的如下：1)构建含有以下成分的载体 兔IL-1ra的分泌型(S)和胞内型(Ic) 获得稳定表达的成肌细胞系或原代 体外培养成肌细胞分泌大量重组IL-1ra 体外；2)肌肉注射，培养的成肌细胞将融合到 与正常肌肉纤维相邻，并会产生大量的分泌物 体内IL-1ra。这些研究将使用最先进的分子 生物技术与有效的免疫分析方法学相结合。这个 这项提案的最终目标是应用从以下方面获得的信息 治疗和预防肝脏和胃肠道炎症的研究 利用基因增强IL-1ra表达的疾病 治疗方法。

Our laboratory has demonstrated that treatment with recombinant IL-1 receptor antagonist (IL-1ra) by repeated injections markedly suppresses inflammation and tissue damage in experimental colitis. In addition, we have recently shown that patients with ulcerative colitis and Crohn's disease have a decreased intestinal IL-1ra/IL-1 ratio compared to normal controls and self-limited infectious colitis, suggesting that patients with inflammatory bowel disease may have a deficit in their ability to produce IL-1ra. Therefore, restoration of the physiological balance between IL-1ra and IL-1 may prove beneficial in reducing intestinal inflammation. Our hypothesis is that development of a cellular transplantation system that can stably produce and deliver recombinant IL-1ra into the systemic circulation may represent an important advance in our ability to treat inflammatory disease, including inflammatory bowel disease and liver diseases in which IL-1 have been shown to play an important role. This hypothesis will be investigated by accomplishing the following specific aims: 1) construct plasmid vectors containing either the secreted(s) or the intracellular (ic) form of rabbit IL-1ra cDNA, and produce stably transfected myogenic cell lines or primary cultured myoblasts synthesizing large amounts of recombinant IL-1ra in vitro; 2) inject intramuscularly, cultured myoblasts that will fuse into adjacent normal muscle fibers and will deliver large amounts of secreted IL-1ra in vivo. These studies will employ state-of-the art molecular biology techniques combined with validated immunoassay methodology. The ultimate goal of this proposal is to apply information derived from these studies to treat and prevent liver and gastrointestinal inflammatory diseases through augmentation of IL-1ra expression by utilizing gene therapy methodologies.