Cardiac arrhythmias occur when the electrical impulses that coordinate heartbeats malfunction. As a result, the heart beats too fast, too slow, or irregularly. In the U.S., nearly one million people are hospitalized for arrhythmias each year. About 300,000 die from sudden arrhythmic death syndrome, which occurs when the heart suddenly fails to pump blood effectively.
Unfortunately, many arrhythmia drugs have serious liabilities, and several have been pulled from the market due to harmful side effects. Mexiletine is one such drug with known risks and potential side effects.
That’s why a CIRM‑funded study led by John Cashman, Ph.D., at the Human BioMolecular Research Institute used $6.3 million to re‑engineer mexiletine to retain its therapeutic effect while reducing toxicity.
The study used induced pluripotent stem cells to model heart disease. Researchers generated iPSCs from a healthy donor and from a patient with an arrhythmia, then converted them into cardiomyocytes.
Using healthy and arrhythmia‑affected cardiomyocytes, Cashman’s team performed “drug development in a dish.” They aimed to reduce drug toxicity while still treating arrhythmias. They modified mexiletine to reduce its toxicity and found it could lower the risk of ventricular tachycardia and ventricular fibrillation.
“The new compounds may lead to treatments for many cardiovascular conditions,” Cashman said in a press release. “As development progresses, we expect these analogs to be less toxic than current arrhythmia drugs, benefiting patients through improved safety, fewer side effects, and potential cost savings.”
The team hopes this strategy—using patient‑specific cells in a dish to reduce toxicity while preserving therapeutic effect—can support future drug development for many diseases.
The full study was published in ACS Publications.
In the early of cell development, stem cells are mobile, they move from one to the other location and search for growth factor which is essential for growth and differentiation. The progenitor cells require various stages of maturation before attaining the late stage of differentiated cells. The mature cells are active, functional and adherence. The adherence of mature cells are depended on cell-surface interaction both with molecules on the surface of the other cells and the extracellular matrix.
The technology of iPSCs derived cardiomacyocytes are considered early stage of stem cells. They are moveable and lack of nerve cells and blood circulation to support their growth and functional. Experimental study to investigate the safety and efficacy of medicine on patients iPSCs organoids may not always translate effective clinical outcome. The early stage of cells are not always have similar cellular structure and molecules to mature cells . Both stages of cells may produce diverse phamacokinetic action against similar drugs. Therefore, the results of experimental study on patients iPSCs organoids with drugs provide very little clinical information to support safety and efficacy of drugs on patients .