Systems approach reveals photosensitivity and PER2 level as determinants of clock‐modulator efficacy

• Published in: Molecular systems biology 2019-07, Vol.15 (7), p.e8838-n/a
• Main Authors: Kim, Dae Wook, Chang, Cheng, Chen, Xian, Doran, Angela C, Gaudreault, Francois, Wager, Travis, DeMarco, George J, Kim, Jae Kyoung
• Format: Article
• Language: English
• Subjects: Animals; Casein Kinase Idelta - antagonists & inhibitors; Casein Kinase Idelta - genetics; Casein Kinase Idelta - metabolism; Circadian Clocks - drug effects; Circadian Clocks - genetics; Circadian Clocks - radiation effects; Circadian Rhythm - drug effects; Circadian Rhythm - genetics; Circadian Rhythm - radiation effects; circadian rhythms; CK1δ/ε inhibitor; Cryptochromes - genetics; Cryptochromes - metabolism; Drug Administration Schedule; Drug Chronotherapy; EMBO10; EMBO33; Gene Expression Regulation; Humans; Light; Light Signal Transduction - genetics; Macaca fascicularis; Mice; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; personalized chronotherapy; Photoperiod; Precision Medicine; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Species Specificity; Systems Biology - methods; systems pharmacology model
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.20198838

In mammals, the master circadian clock synchronizes daily rhythms of physiology and behavior with the day–night cycle. Failure of synchrony, which increases the risk for numerous chronic diseases, can be treated by phase adjustment of the circadian clock pharmacologically, for example, with melatonin, or a CK1δ/ε inhibitor. Here, using in silico experiments with a systems pharmacology model describing molecular interactions, and pharmacokinetic and behavioral experiments in cynomolgus monkeys, we find that the circadian phase delay caused by CK1δ/ε inhibition is more strongly attenuated by light in diurnal monkeys and humans than in nocturnal mice, which are common preclinical models. Furthermore, the effect of CK1δ/ε inhibition strongly depends on endogenous PER2 protein levels, which differs depending on both the molecular cause of the circadian disruption and the patient's lighting environment. To circumvent such large interindividual variations, we developed an adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions. Our results reveal the importance of photosensitivity in the clinical efficacy of clock‐modulating drugs, and enable precision medicine for circadian disruption. Synopsis The study identifies the sources of the inter‐ and intraspecies variability in the modulation of circadian phase by CK1δ/ε inhibition: photosensitivity and PER2 abundance, and proposes a personalized chronotherapy to treat circadian disruption. Light attenuates the effect of CK1δ/ε inhibition more strongly in diurnal monkeys than in nocturnal mice. The effect of CK1δ/ε inhibition becomes stronger as PER2 protein abundance increases, which leads to a large interindividual variability in circadian phase shift. To circumvent such large interindividual variability, an adaptive chronotherapeutic approach is developed, which identifies a personalized dosing time by tracking the patient's drug response. Graphical Abstract The study identifies the sources of the inter‐ and intraspecies variability in the modulation of circadian phase by CK1δ/ε inhibition: photosensitivity and PER2 abundance, and proposes a personalized chronotherapy to treat circadian disruption.