Genetically-engineered stem cells for self-regulating arthritis therapy

Abstract Arthritis-related conditions occur in over 1 in 5 adults, and the prevalence is increasing. Current approaches to modulate endogenous inflammatory mediators in rheumatoid arthritis (RA) predispose patients to significant adverse effects (AEs), such as infection, when anti-cytokine biologic drugs are delivered continually at fixed doses. As the severity of RA fluctuates over time, development of specific therapeutic strategies that can sense and respond to varying levels of endogenous inflammatory mediators by producing correspondingly appropriate levels of anti-cytokine drugs represents an attractive alternative approach that may mitigate AEs induced by continuous biologic administration. The goal of this project is to used genetically engineered stem cells to create bioartificial implants for biologic drug delivery as a therapy for RA. By combining principles of synthetic biology and tissue engineering, we will develop stem cells that respond to specific pro-inflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor alpha by producing targeted anti-cytokine drugs in a feedback-controlled, self-regulating, and multiplexed manner. A primary focus of this study is to fine-tune these reprogrammed anti-inflammatory cells to enhance the sensitivity and specificity of cell-based drug delivery in response to low-level systemic inflammation. Synthetic gene circuits will also be introduced in these cells to allow for exogenously-controlled tunable and inducible safety switches that can temporarily or permanently disable anti-cytokine drug production. These engineered cells will be encapsulated in agarose-based implants that will be placed subcutaneously in mice induced with experimental RA, and the long-term safety and efficacy of these approaches will be assessed using clinical, histologic, molecular, and pain/behavior testing. The creation of such “designer” cells provides the possibility for long-term, feedback-controlled drug delivery for the treatment of chronic inflammatory diseases.