| abstract |
This invention relates to the therapeutic induction of apoptosis in activated inflammatory cells, or cells at a site of inflammation, by introducing into those cells a chimeric gene containing an apoptosis-inducing gene (AIG) driven by a promoter of an inducible gene activated in inflammation and a promoter enhancer such that the inflammatory cells are targeted. In one embodiment, the chimeric gene comprises at least one TNF.alpha. promoter enhancer attached to a functional copy of a minimal TNF.alpha. promoter and further attached to at least one copy of an apoptosis-inducing gene, wherein expression of the gene is driven by the TNF.alpha. promoter. Attachment can be direct, distal, proximal or combinations thereof. Example apoptosis-inducing genes include caspase 3, caspase 4, caspase 5, Granzyme B. Advantageously, the TNFp-AIG chimeric gene is expressed in only those cells producing the inflammatory cytokine, TNF.alpha.. In addition, the TNFp-AIG chimeric gene also sequesters inducible TNFp transcription factors, thereby reducing endogenous production of TNF.alpha.. The invention also relates to methods of making and using selfregulated apoptosis chimeric genes and pharmaceutical compositions containing them for treating inflammatory diseases. |