Precision Drug Design: Using patient cells to improve treatments

By Amanda Chase, PhD
September 14, 2020

Fourteen years ago, it was found that skin or blood cells could be turned back into an embryonic-like type of cell that can then be turned into any other cell type. These cells, called induced pluripotent stem cells (iPSCs), can be directed to become specific types of adult cells, such as heart cells (cardiomyocytes [CMs]) or neurons. Importantly, differentiated cells derived from iPSCs recapitulated disease features of the patients not seen in cells from healthy patients. The reproduction of human disease in a cell culture dish makes it possible to directly evaluate the effects of new drugs that are under development on patient cells, without the risk of treating the patients themselves.

Despite the promise iPSCs hold for the drug discovery, only a few large-scale drug development efforts have used iPSCs, and they were done in healthy donors. A group of researchers, led by Stanford Cardiovascular Institute affiliated first author Wesley McKeithan, PhD, and senior-author Mark Mercola, PhD, describe for the first time the use of iPSCs in large-scale drug development in the journal Cell Stem Cell, in their paper "Reengineering an antiarrhythmic drug using patient hiPSC-cardiomyocytes to improve therapeutic potential and reduce toxicity." Their study, conducted in collaboration with the medicinal chemistry laboratory of John Cashman, PhD, of the Human BioMolecular Research Institute in San Diego, CA, used heart cells from patients with a heart rhythm disorder to chemically refine a drug used to treat the disease, showing the potential for precision drug design.

Human cardiomyocytes derived in vitro from induced pluripotent stem cells (iPSCs). Membranes are stained with a fluorescent probe (WGA). Video by Francesca Briganti, PhD.

Long QT syndrome (LQTS) is a heart rhythm disorder that can cause fast, chaotic heartbeats. It represents a leading cause of sudden death in younger patients. Without therapy, LQTS has a high mortality rate within 1 year. However, with treatment, mortality is significantly decreased, down to ~1% over 15 years. Mexiletine is one such drug that works to stabilize the heart rhythm and is considered to be an especially good therapy for certain forms of LQTS. While mexiletine is good at stabilizing heart rate, it is not without side effects. iPSCs turned into cardiomyocytes (iPSC-CMs), especially from patients with LQTS, provide a unique opportunity to look at how well drugs like mexiletine stabilize the heart rhythm as well as any side effects in the heart cell and provides the opportunity to identify potentially improved treatments.

"Drugs for heart disease are typically developed using overly simplified models, like tumor cells engineered in a specific way to mimic a biochemical event. Consequently, drugs like this one, mexiletine, have undesirable properties of concern in treating patients," explains Dr. Mercola. "Here, we used cells from a patient to generate that person's heart muscle cells in a dish so we could visualize both the good and bad effects of the drug."

The research team examined newly created drug candidates that were similar in structure to mexiletinebut with some chemical differences (structural analogues). They then used the iPSC-CMs to test these analogues in a large-scale manner. Using cells from a patient with LQTS, they were able to determine how well the drug candidates could stabilize the heartbeat and determine whether any were more effective than mexiletine. Importantly, the researchers used iPSCs from healthy individuals to also test if there were any unwanted side effects. "We used this information in an iterative process to test many structural analogues of mexiletine to discover the reasons for the good and bad effects and ultimately design a better version," says Dr. Cashman.

Ultimately, the team was able to identify several refined versions of mexiletine with superior pharmacological and pharmaceutical properties. Perhaps more importantly, for the first time they were able to show that iPSC-CMs from patients with a specific disease can be used to guide drug improvement and optimization in a large-scale manner. "Our approach shows the feasibility of introducing human disease models early in the drug development pipeline and opens the door for precision drug design to improve therapies for patients," says Dr. McKeithan, lead author of the study.

Other Stanford Cardiovascular-affiliated authors include Dries Feyan, Arne Bruyneel, Alex Savchenko, Michelle Vu, and Ricardo Serrano. Other Human BioMolecular Research Institute-affiliated authors include Karl Okolotowicz, Daniel Ryan, and Jorge Gómez-Galeno. The team also include researchers in the labs of Alfred George, Jr. at Northwestern University, and Robert S. Kass at Columbia University.

Figure: Induced pluripotent stem cells (iPSCs) from a LQTS patient or a healthy individual were directed to become heart muscle cells (iPSC-CMs). These cells were used to screen drugs similar to mexiletine, a therapy for LQTS. Several refined versions of mexiletine were identified, demonstrating the ability of iPSC-CMs to be used as human disease models in the drug development pipeline.

Dr. Wesley McKeithan

Dr. Mark Mercola