A Synthetic Chrono Genetic Therapy Gene for Consecutive Drug Delivery

Abstract

Chronotherapy, the delivery of therapeutic interventions personalized to patient's circadian rhythms, has shown enhanced therapeutic efficacy and reduced side effects. Patients exhibit diurnal changes in cytokines in rheumatoid arthritis that lead to inflammatory flares and enhanced disease severity in the early morning. There has been important work showing the administration of anti-inflammatory treatments in the early morning, immediately before the inflammatory flare, in reducing symptoms of RA. Using synthetic biology, we developed chronotherapy-based gene chromogenic therapies that produce our prescribed transgene downstream of the core circadian clock component, Per2. We transduced these lentiviral chromogenic therapies into murine-induced pluripotent stem cells and developed tissue-engineered cartilage as our model system for timed drug delivery. Our anti-inflammatory chromogenic could produce interleukin-1 receptor antagonist (IL-1Ra) in an oscillatory manner tracking with circadian rhythms in vitro. Additionally, the tissue-engineered pellets could entrain host circadian rhythms when implanted into mice and produce different levels of IL-1Ra in the serum at other times of the day. The chromogenic synthetic gene provides a novel cell therapy driving by the circadian clock for controlled biologic delivery at prescribed times of the day.