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

我们的实验室已经证明重组 IL-1 治疗 受体拮抗剂（IL-1ra）通过重复注射可显着抑制 实验性结肠炎的炎症和组织损伤。 此外，我们 最近的研究表明，患有溃疡性结肠炎和克罗恩病的患者 与正常人相比，疾病患者的肠道 IL-1ra/IL-1 比率降低 控制和自限性感染性结肠炎，表明患者 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 之间的关系可能被证明有益于减少肠道 炎症。 我们的假设是细胞的发育 能够稳定生产和递送重组体的移植系统 IL-1ra进入体循环可能代表着一项重要进展 我们治疗炎症性疾病的能力，包括炎症 IL-1 已被证明在肠道疾病和肝脏疾病中发挥作用 一个重要的角色。 该假设将通过完成来进行研究 具体目的如下： 1）构建含有 兔 IL-1ra 的分泌形式或细胞内 (ic) 形式 cDNA，并产生稳定转染的生肌细胞系或原代 培养的成肌细胞在体内合成大量重组IL-1ra 体外； 2）肌肉注射培养的成肌细胞，它们将融合成 邻近的正常肌纤维，并会输送大量分泌的 体内IL-1ra。 这些研究将采用最先进的分子 生物学技术与经过验证的免疫测定方法相结合。 的 该提案的最终目标是应用从这些数据中获得的信息 治疗和预防肝脏和胃肠道炎症的研究 利用基因增强 IL-1ra 表达引起的疾病 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.