Inflammation-responsive promoters for fine-tuned gene therapy in rheumatoid arthritis

The inflamed joints of rheumatoid arthritis (RA) patients are ideally suited for gene therapy applications that induce local production of potent anti-inflammatory biologicals. The precise and absolute targeting needed when treating cancer is not necessary in RA. However, the challenge is to regulate transgene expression to meet variable physiological demands during the intermittent course of the disease in RA patients. Thus, a biosensing system with an inducible transcriptional switch that allows robust but adjustable transgene expression is required. Inflammation-inducible promoters are likely candidates to achieve precise control of transgene expression by physiologically driven processes. Acute-phase proteins, pro-inflammatory cytokines, heatshock proteins and hypoxia-responsive genes are all related to the pathogenesis of RA, and their promoters can be exploited for disease-inducible transgene expression. With this, gene therapy enters a new era, that of temporal control of the therapeutic transgene expression. In addition to the reversible transcriptional switch, the ideal expression system also contains an amplification loop for high transgene expression and a drug-controllable switch to allow intervention by the physician. The merging of these modalities may provide a flexible system to fine-tune transgene expression, which is a prerequisite for the implementation of gene therapy in RA.