Pursuing Treatments

via Modulation of Biological Clocks

Circadian dysfunction is involved in the pathologies of various diseases, including cardiovascular, metabolic, and central nervous system disorders; immune system dysfunction; and cancer.

The Need for a New Treatment Paradigm

Diabetes, obesity, and other metabolic disorders alone affect millions of people, many of whom could benefit from novel therapies that target the molecular causes of disease, rather than just treating symptoms. Data suggest that resetting molecular clock activity resynchronizes biologic demands and environmental signals, and provides a novel approach to treating diseases that impact large and diverse patient populations.

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Cushing's Syndrome

Hypercortisolism (Cushing’s syndrome) develops due to extended exposure to excessive exogenous or endogenous glucocorticoids. Glucocorticoid excess results in metabolic complications from high glucose production. Common symptoms include weight gain; fatty deposits in the face (moon face), upper back, and midsection; thinning arms and legs; and fragile skin. Most patients also have severe fatigue, weak muscles, high blood pressure, and high blood sugar.

Cortisol is a glucocorticoid made by the adrenal gland, and its release normally follows a clear circadian pattern with a peak in the morning and nadir in late evening. Cushing’s patients lack the late evening nadir. A class of proteins called cryptochromes promotes glucose homeostasis and balances the hypothalamic-pituitary-adrenal axis through time-of-day dependent modulation of the glucocorticoid receptor. Reset’s small-molecule cryptochrome stabilizers will restore normal circadian alignment to cortisol rhythms and mitigate the negative downstream consequences of the disease, including hyperglycemia and hypertension.

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Diabetes

Cryptochrome proteins help keep the liver’s production of glucose in sync with fasting at night and eating during the day. Reset will diminish the pathophysiology associated with metabolic disorders by restoring rhythms through the development of cryptochrome modulators.

Clocks play a fundamental role in metabolic regulation, and rhythmic coordination is essential for liver, pancreatic β-cells, and other tissues. Disruption of core clock elements results in inappropriate gluconeogenesis in liver and diminished insulin secretion from pancreatic β-cells. Cryptochrome proteins help keep the liver’s production of glucose in sync with fasting at night and eating during the day. Reset will diminish the pathophysiology associated with metabolic disorders by restoring rhythms through the development of cryptochrome modulators.

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Narcolepsy

Orexin neuropeptides are the biological on/off switch, key modulators of clock output in the brain, affecting sleep/wake cycles and energy balance. Reset will improve the treatment of narcolepsy through the development of orexin receptor modulators.

Orexin neurons are found only in the lateral hypothalamic area and project to the entire central nervous system. Narcolepsy patients have reduced orexin neurons and reduced orexin levels but maintain the post-synaptic receptors. Orexin-A promotes wakefulness; by enhancing the effects of orexin-A, small molecule orexin receptor modulators will diminish the excessive daytime sleepiness (EDS) and cataplexy suffered by narcoleptic patients. There are also development opportunities for other disorders associated with EDS and cognition, such as Parkinson’s disease.

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