Researchers at WashU Medicine have harnessed the internal circadian clock of the body to deliver medication for an inflammatory illness precisely when it was most needed. Tissue implants incorporating genetically engineered stem cells automatically delivered anti-inflammatory medications to mouse models of rheumatoid arthritis on a daily basis right before inflammation peaked. The researchers dubbed this approach "chronogenetics."
The research was published Feb. 7 in Nature Communications.
Inflammatory flares in rheumatoid arthritis are triggered by changes in the levels of infection-fighting proteins in the body. The levels of these proteins fluctuate over the course of the day, as dictated by circadian signals driven by our normal 24-hour light-dark cycle. A team led by Farshid Guilak, the Mildred B. Simon Research Professor of Orthopaedic Surgery at WashU Medicine, developed a specialized stem cell implant that carried a synthetic gene circuit that was programmed to activate and release anti-inflammatory medication when the circadian signal turned on.
The therapeutic implants, which consisted of the reprogrammed stem cells engineered into cartilage constructs, effectively treated inflammatory flare-ups for up to a month in mice. The implanted gene switches were adaptable as well: when the mice's sleep schedule was reversed from sleeping during the day to sleeping at night, the cells rapidly resynchronized to the new circadian pattern.
In humans with rheumatoid arthritis, painful inflammation triggered by the body's daily rhythms might occur at 3 a.m., making it very difficult for patients to treat their symptoms effectively. If successfully adapted for humans, the chronogenetic approach could treat rheumatoid arthritis at the optimal circadian moment. Guilak and his team have received funding from Advanced Research Projects Agency for Health (ARPA-H) to develop this approach for clinical trials in human patients. Guilak has applied for a patent for the technique developed in this study. He is an also an employee and shareholder in Cytex Therapeutics Inc., which is developing the cartilage-based structures used in this study for therapeutic use.
