Nav: Home

Mathematical modeling for translational research of new CRSD medication

July 09, 2019

Mathematicians' new modeling has identified major sources of interspecies and inter-individual variations in the clinical efficacy of a clock-modulating drug: photosensitivity and PER2 level. This enabled precision medicine for circadian disruption.

A KAIST mathematics research team led by Professor Jae Kyoung Kim, in collaboration with Pfizer, applied a combination of mathematical modeling and simulation tools for circadian rhythms sleep disorders (CRSDs) to analyze the animal data generated by Pfizer. This study was reported in Molecular Systems Biology as the cover article on July 8.

Pharmaceutical companies have conducted extensive studies on animals to determine the candidacy of this new medication. However, the results of animal testing do not always translate to the same effects in human trials. Furthermore, even between humans, efficacy differs across individuals depending on an individual's genetic and environmental factors, which require different treatment strategies.

To overcome these obstacles, KAIST mathematicians and their collaborators developed adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions.

A circadian rhythm is a 24-hour cycle in the physiological processes of living creatures, including humans. A biological clock in the hypothalamic suprachiasmatic nucleus in the human brain sets the time for various human behaviors such as sleep.

A disruption of the endogenous timekeeping system caused by changes in one's life pattern leads to advanced or delayed sleep-wake cycle phase and a desynchronization between sleep-wake rhythms, resulting in CRSDs. To restore the normal timing of sleep, timing of the circadian clock could be adjusted pharmacologically.

Pfizer identified PF-670462, which can adjust the timing of circadian clock by inhibiting the core clock kinase of the circadian clock (CK1d/e). However, the efficacy of PF-670462 significantly differs between nocturnal mice and diurnal monkeys, whose sleeping times are opposite.

The research team discovered the source of such interspecies variations in drug response by performing thousands of virtual experiments using a mathematical model, which describes biochemical interactions among clock molecules and PF-670462. The result suggests that the effect of PF-670462 is reduced by light exposure in diurnal primates more than in nocturnal mice. This indicates that the strong counteracting effect of light must be considered in order to effectively regulate the circadian clock of diurnal humans using PF-670462.

Furthermore, the team also found the source of inter-patients variations in drug efficacy using virtual patients whose circadian clocks were disrupted due to various mutations. The degree of perturbation in the endogenous level of the core clock molecule PER2 affects the efficacy.

This explains why the clinical outcomes of clock-modulating drugs are highly variable and certain subtypes are unresponsive to treatment. Furthermore, this points out the limitations of current treatment strategies tailored to only the patient's sleep and wake time but not to the molecular cause of sleep disorders.

PhD candidate Dae Wook Kim, who is the first author, said that this motivates the team to develop an adaptive chronotherapy, which identifies a personalized optimal dosing time of day by tracking the sleep-wake up time of patients via a wearable device and allows for a precision medicine approach for CRSDs.

Professor Jae Kyoung Kim said, "As a mathematician, I am excited to help enable the advancement of a new drug candidate, which can improve the lives of so many patients. I hope this result promotes more collaborations in this translational research."
-end-
This research was supported by a Pfizer grant to KAIST (G01160179), the Human Frontiers Science Program Organization (RGY0063/2017), and a National Research Foundation (NRF) of Korea Grant (NRF-2016 RICIB 3008468 and NRF-2017-Fostering Core Leaders of the Future Basic Science Program/ Global Ph.D. Fellowship Program).

The Korea Advanced Institute of Science and Technology (KAIST)

Related Sleep Articles:

Wind turbine noise affects dream sleep and perceived sleep restoration
Wind turbine noise (WTN) influences people's perception of the restorative effects of sleep, and also has a small but significant effect on dream sleep, otherwise known as REM (rapid eye movement) sleep, a study at the University of Gothenburg, Sweden, shows.
To sleep deeply: The brainstem neurons that regulate non-REM sleep
University of Tsukuba researchers identified neurons that promote non-REM sleep in the brainstem in mice.
Chronic opioid therapy can disrupt sleep, increase risk of sleep disorders
Patients and medical providers should be aware that chronic opioid use can interfere with sleep by reducing sleep efficiency and increasing the risk of sleep-disordered breathing, according to a position statement from the American Academy of Sleep Medicine.
'Short sleep' gene prevents memory deficits associated with sleep deprivation
The UCSF scientists who identified the two known human genes that promote 'natural short sleep' -- nightly sleep that lasts just four to six hours but leaves people feeling well-rested -- have now discovered a third, and it's also the first gene that's ever been shown to prevent the memory deficits that normally accompany sleep deprivation.
Short sleep duration and sleep variability blunt weight loss
High sleep variability and short sleep duration are associated with difficulties in losing weight and body fat.
Nurses have an increased risk of sleep disorders and sleep deprivation
According to preliminary results of a new study, there is a high prevalence of insufficient sleep and symptoms of common sleep disorders among medical center nurses.
Common sleep myths compromise good sleep and health
People often say they can get by on five or fewer hours of sleep, that snoring is harmless, and that having a drink helps you to fall asleep.
Sleep tight! Researchers identify the beneficial role of sleep
Why do animals sleep? Why do humans 'waste' a third of their lives sleeping?
Does extra sleep on the weekends repay your sleep debt? No, researchers say
Insufficient sleep and untreated sleep disorders put people at increased risk for metabolic problems, including obesity and diabetes.
Kicking, yelling during sleep? Study finds risk factors for violent sleep disorder
Taking antidepressants for depression, having post-traumatic stress disorder or anxiety diagnosed by a doctor are risk factors for a disruptive and sometimes violent sleep disorder called rapid eye movement (REM) sleep behavior disorder, according to a study published in the Dec.
More Sleep News and Sleep Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.