Timed dosing of therapeutic compounds to maximize the efficacy of therapeutics while reducing undesired adverse effects.
Circadian rhythms are endogenous 24-hour oscillations in behavior and biological processes that respond primarily to light and darkness. The circadian clock drives oscillations in many processes, including sleep, locomotor activity, blood pressure, body temperature, and blood hormone levels. However, how the circadian clock regulates human physiology and pathophysiology is largely unknown.
In efforts to leverage biological time during drug development, Penn researchers investigated how gene expression in mouse organs changes over time and discovered that ~50% of protein-coding genome is expressed in a circadian clock dependent manner. Importantly, the majority of best-selling drugs and World Health Organization essential medicines directly target clock-regulated gene products. Since many of these drugs have short half-lives, they could greatly benefit from temporal dosing.
This information can be used to developing delayed-release formulations of therapeutics so that the time of release coincides with the highest expression of the drug target or transporter. The converse is also possible, timing a drug to avoid its rapid metabolism. This chronotherapy could be used to reduce off-target as well as adverse effects while increasing on-target efficacy. This invention applies to many drugs, diseases, and health conditions.
Circadian disease genes and drug targets. (A) Overlap between circadian genes, known disease-associated genes, and drug targets. (B) Example of a common drug having an oscillatory gene target: expression profiles for the aspirin target Ptgs1 from heart, lung, and kidney. Traces from these organs for the mir22 host gene, predicted to target Ptgs1, are also shown. This may underlie the time-dependent hypotensive effect of low dose aspirin. Note: Figure is from Zhang et al.
PNAS, 2014, 111 (45) – 16219