Article Impact Level: HIGH Data Quality: STRONG Summary of Nature Communications, 16(1), 1457. https://doi.org/10.1038/s41467-025-56584-5 Dr. Lara Pferdehirt et al.
Points
- Researchers developed chronogenetic interventions that align drug release with the body’s circadian rhythms, improving treatment efficacy for rheumatoid arthritis (RA) and other inflammatory diseases.
- Scientists engineered gene circuits within induced pluripotent stem cells (iPSCs) and integrated them into tissue-engineered cartilage constructs to produce interleukin-1 receptor antagonists in sync with natural inflammatory cycles.
- Implanted constructs adapted to daily light cycles and produced biologic drugs in alignment with Per2 gene expression, which correlates with peak inflammatory flare-ups in RA patients.
- This cell-based chronogenetic therapy could be applied to cancer, diabetes, and other circadian-influenced conditions, optimizing treatment timing to preempt disease flares and enhance therapeutic outcomes.
- Human trials are expected within 3–5 years. They will apply to both pediatric and adult patients and potentially transform chronic disease management through personalized, time-sensitive drug delivery.
Summary
In recent studies, circadian-based therapeutic interventions have shown promise in improving the efficacy and minimizing side effects of treatments for diseases like rheumatoid arthritis (RA) and other inflammatory conditions. These diseases exhibit diurnal cytokine variations, with peak inflammation typically occurring in the early morning. A new approach called “chronogenetics” has been developed to address this. Researchers utilized synthetic biology and tissue engineering to create gene circuits that express therapeutic transgenes based on an individual’s circadian rhythms. These gene circuits were integrated into induced pluripotent stem cells (iPSCs) and tissue-engineered into cartilage constructs. In vitro, these chronogenetic constructs produced interleukin-1 receptor antagonists at therapeutic concentrations.
In vivo, the implanted constructs exhibited circadian rhythms and entrained to daily light cycles, producing biologic drugs in alignment with the body’s natural rhythms. Notably, drug production peaked at the time of Per2 gene expression, mirroring the inflammatory flare-ups in RA. This chronogenetic system was shown to deliver drugs at a most beneficial time to patients, potentially preempting the daily disease flares typically observed in inflammatory diseases. These findings open the door to applications in other circadian-influenced conditions, such as cancer and diabetes, where disease progression is similarly linked to circadian variations.
The development of this cell-based chronogenetic therapy has significant implications for chronic disease management. By providing targeted drug delivery timed to individual circadian rhythms, this approach may alleviate symptoms and prevent disease progression, offering a novel treatment avenue that could transform how inflammatory diseases like RA are managed in the future. Clinical trials are expected to begin within 3–5 years, with potential applications for pediatric and adult patients with arthritis and other diseases.
Link to the article: https://www.nature.com/articles/s41467-025-56584-5
References Pferdehirt, L., Damato, A. R., Lenz, K. L., Gonzalez-Aponte, M. F., Palmer, D., Meng, Q.-J., Herzog, E. D., & Guilak, F. (2025). A synthetic chronogenetic gene circuit for programmed circadian drug delivery. Nature Communications, 16(1), 1457. https://doi.org/10.1038/s41467-025-56584-5
