A synthetic chronogenetic gene circuit for programmed circadian drug delivery
Abstract Circadian medicine, the delivery of therapeutic interventions based on an individual’s daily rhythms, has shown improved efficacy and reduced side-effects for various treatments. Rheumatoid arthritis and other inflammatory diseases are characterized by diurnal changes in cytokines, leading...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56584-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861788977922048 |
|---|---|
| author | Lara Pferdehirt Anna R. Damato Kristin L. Lenz Maria F. Gonzalez-Aponte Daniel Palmer Qing-Jun Meng Erik D. Herzog Farshid Guilak |
| author_facet | Lara Pferdehirt Anna R. Damato Kristin L. Lenz Maria F. Gonzalez-Aponte Daniel Palmer Qing-Jun Meng Erik D. Herzog Farshid Guilak |
| author_sort | Lara Pferdehirt |
| collection | DOAJ |
| description | Abstract Circadian medicine, the delivery of therapeutic interventions based on an individual’s daily rhythms, has shown improved efficacy and reduced side-effects for various treatments. Rheumatoid arthritis and other inflammatory diseases are characterized by diurnal changes in cytokines, leading to inflammatory flares, with peak disease activity in the early morning. Using a combination of synthetic biology and tissue engineering, we developed circadian-based gene circuits, termed “chronogenetics”, that express a prescribed transgene downstream of the core clock gene promoter, Period2 (Per2). Gene circuits were transduced into induced pluripotent stem cells that were tissue-engineered into cartilage constructs. Our anti-inflammatory chronogenetic constructs produced therapeutic concentrations of interleukin-1 receptor antagonist in vitro. Once implanted in vivo, the constructs expressed circadian rhythms and entrained to daily light cycles, producing daily increases in biologic drug at the peak of Per2 expression. This approach represents the development of a cell-based chronogenetic therapy for various applications in circadian medicine. |
| format | Article |
| id | doaj-art-2a4992197d974595bea3f787fb0fdad7 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2a4992197d974595bea3f787fb0fdad72025-02-09T12:44:59ZengNature PortfolioNature Communications2041-17232025-02-0116111110.1038/s41467-025-56584-5A synthetic chronogenetic gene circuit for programmed circadian drug deliveryLara Pferdehirt0Anna R. Damato1Kristin L. Lenz2Maria F. Gonzalez-Aponte3Daniel Palmer4Qing-Jun Meng5Erik D. Herzog6Farshid Guilak7Department of Orthopedic Surgery, Washington University School of MedicineDepartment of Biology, Washington UniversityDepartment of Orthopedic Surgery, Washington University School of MedicineDepartment of Biology, Washington UniversityDepartment of Orthopedic Surgery, Washington University School of MedicineWellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of ManchesterDepartment of Biology, Washington UniversityDepartment of Orthopedic Surgery, Washington University School of MedicineAbstract Circadian medicine, the delivery of therapeutic interventions based on an individual’s daily rhythms, has shown improved efficacy and reduced side-effects for various treatments. Rheumatoid arthritis and other inflammatory diseases are characterized by diurnal changes in cytokines, leading to inflammatory flares, with peak disease activity in the early morning. Using a combination of synthetic biology and tissue engineering, we developed circadian-based gene circuits, termed “chronogenetics”, that express a prescribed transgene downstream of the core clock gene promoter, Period2 (Per2). Gene circuits were transduced into induced pluripotent stem cells that were tissue-engineered into cartilage constructs. Our anti-inflammatory chronogenetic constructs produced therapeutic concentrations of interleukin-1 receptor antagonist in vitro. Once implanted in vivo, the constructs expressed circadian rhythms and entrained to daily light cycles, producing daily increases in biologic drug at the peak of Per2 expression. This approach represents the development of a cell-based chronogenetic therapy for various applications in circadian medicine.https://doi.org/10.1038/s41467-025-56584-5 |
| spellingShingle | Lara Pferdehirt Anna R. Damato Kristin L. Lenz Maria F. Gonzalez-Aponte Daniel Palmer Qing-Jun Meng Erik D. Herzog Farshid Guilak A synthetic chronogenetic gene circuit for programmed circadian drug delivery Nature Communications |
| title | A synthetic chronogenetic gene circuit for programmed circadian drug delivery |
| title_full | A synthetic chronogenetic gene circuit for programmed circadian drug delivery |
| title_fullStr | A synthetic chronogenetic gene circuit for programmed circadian drug delivery |
| title_full_unstemmed | A synthetic chronogenetic gene circuit for programmed circadian drug delivery |
| title_short | A synthetic chronogenetic gene circuit for programmed circadian drug delivery |
| title_sort | synthetic chronogenetic gene circuit for programmed circadian drug delivery |
| url | https://doi.org/10.1038/s41467-025-56584-5 |
| work_keys_str_mv | AT larapferdehirt asyntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT annardamato asyntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT kristinllenz asyntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT mariafgonzalezaponte asyntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT danielpalmer asyntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT qingjunmeng asyntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT erikdherzog asyntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT farshidguilak asyntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT larapferdehirt syntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT annardamato syntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT kristinllenz syntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT mariafgonzalezaponte syntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT danielpalmer syntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT qingjunmeng syntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT erikdherzog syntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery AT farshidguilak syntheticchronogeneticgenecircuitforprogrammedcircadiandrugdelivery |