Adjusting to a new time zone or work schedule can leave the body's internal clock out of sync for days, contributing to sleep disruption, metabolic changes and other health consequences. Researchers at Rice University, with the support of the Rice Biotech Launch Pad , and Northwestern University have developed an implantable cell therapy that may help the body adapt more quickly to these disruptions.
In a recent study titled " Encapsulated Leptin-Producing Cells Facilitate Entrainment of Circadian Rhythms in Rodents and Nonhuman Primates ," encapsulated cells engineered to continuously produce the metabolic hormone leptin reduced the time required for animals to adjust to shifts in the light-dark cycle that mimic jet lag and shift work. Published in Advanced Science, the study's findings demonstrate a new approach to regulating circadian rhythms through metabolic signaling and provide early evidence that engineered cell therapies could be used to address circadian disruption.
"Current approaches for adjusting circadian rhythms rely heavily on precisely timed behaviors such as light exposure, meal schedules or melatonin administration," said Omid Veiseh , professor of bioengineering at Rice and faculty director of the Rice Biotech Launch Pad. "We wanted to explore whether a temporary cell therapy could provide a more practical way to help the body adapt to changing schedules."
The therapy consists of human retinal pigment epithelial cells engineered to produce leptin, a hormone best known for regulating appetite and metabolism. The cells are encapsulated within microscopic alginate spheres that protect them from the immune system while allowing therapeutic proteins to diffuse into the body. Following a simple subcutaneous injection, the encapsulated cells temporarily elevate circulating leptin levels before naturally losing viability over time.
"Metabolism and circadian rhythms are closely connected, but the therapeutic potential of that relationship remains largely unexplored," said Martha Hotz Vitaterna, professor of neurobiology at Northwestern University and co-corresponding author on the study. "These findings suggest that metabolic signals can be leveraged to accelerate adaptation to circadian disruptions."
In mouse studies, animals receiving the leptin-producing cell therapy adjusted significantly faster following both phase advances and phase delays in the light-dark cycle. Mice treated with the therapy adapted to a four-hour schedule delay 50% faster days than in control animals.
To evaluate the translational potential of the approach, the researchers tested the therapy in cynomolgus macaques, whose sleep-wake patterns more closely resemble those of humans. The treatment was well tolerated and reduced entrainment time following six-hour schedule shifts by approximately one day compared to controls.
"The fact that we observed similar effects in both rodents and non-human primates suggests that the underlying biology may be conserved across species," said Fred Turek, director of Northwestern's Center for Sleep and Circadian Biology and a senior author on the study.
Researchers monitored multiple physiological indicators of circadian alignment, including activity, heart rate and core body temperature. Across these measures, animals receiving the leptin-producing implants adapted more rapidly to the new schedules than untreated controls.
Importantly, the therapy did not negatively affect sleep. Analysis of sleep architecture in non-human primates showed no reduction in total sleep time, rapid eye movement sleep or non-REM sleep. Researchers also observed increases in slow-wave sleep activity following some schedule shifts, suggesting a potential improvement in sleep quality during recovery.
Beyond demonstrating efficacy, the study also evaluated the safety and practicality of the platform. Blood tests and clinical monitoring showed no signs of significant toxicity in non-human primates, and animals receiving multiple doses over the course of a year experienced no long-term adverse effects. The encapsulated cells remained active for several days before naturally declining, creating a temporary and reversible intervention.
"Our goal was not to permanently alter the circadian system," Samantha Fleury, first author on the publication, said. "We wanted a therapy that could provide short-term support during periods of disruption and then naturally resolve."
The researchers believe the platform could eventually be explored for applications involving frequent circadian disruption, including shift work, military operations, international travel and other situations where rapid adaptation to changing schedules is important.
"This work provides further evidence that metabolic pathways can be harnessed to influence circadian biology," said Jonathan Rivnay, professor of biomedical engineering and materials science and engineering at Northwestern University and a senior author on the study. "More broadly, it demonstrates how engineered cell therapies can be used to deliver biologically active molecules in ways that would be difficult to achieve through conventional dosing."
The team plans to further investigate the mechanisms linking leptin and circadian regulation and explore next-generation versions of the platform capable of providing tunable or repeatable circadian support.
The research was supported by the 711th Human Performance Wing and the Defense Advanced Research Projects Agency under agreement number FA8650-21-1-7119.
