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

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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.