Mexiletine

CIRM funded study uses drug development in a dish for treatment of heart arrhythmias

/ Yimy Villa / 1 Comment
Image Credit: Center for Disease Control and Prevention (CDC)

Cardiac (heart) arrhythmias occur when electrical impulses that coordinate your heartbeats don’t work properly, causing your heart to beat too fast, too slow, or in an irregular manner. In the U.S. alone, almost one million individuals are hospitalized every year for heart arrhythmias. Close to 300,000 individuals die of sudden arrhythmic death syndrome every year, which occurs when there is a sudden loss of blood flow resulting from the failure of the heart to pump effectively. Unfortunately, drugs to treat arrhythmias have liabilities and several drugs have been pulled from the market due to serious side effects. Mexiletine is one potential drug for heart arrhythmias that has liabilities and potential side effects.

That is why a CIRM funded study ($6.3 million) conducted by John Cashman, Ph.D. at the Human BioMolecular Research Institute in San Diego looked at re-engineering mexiletine in a way that the drug could still produce a desired result and not be as toxic.

The study used induced pluripotent stem cells (iPSCs), a type of stem cell “reprogrammed” from the skin or blood of patients that can be used to make virtually any kind of cell. iPSCs obtained for the study were from a healthy patient and from one with a type of heart arrhythmia. The healthy and arrhythmia iPSCs were then converted into cardiomyocytes, a type of cell that makes up the heart muscle.

By using their newly created healthy cardiomyocytes and those with the arrhythmia defect, Cashman and his team were able to carry out drug development in a dish. This enabled them to attempt to lessen drug toxicity while still potentially treating heart arrhythmias. The team was able to modify mexiletine such that is was less toxic and found that it could potentially decrease a patient’s risk of developing ventricular tachycardia (a fast, abnormal heart rate) and ventricular fibrillation (an abnormal heart rhythm), both of which are types of heart arrhythmias.

“The new compounds may lead to treatment applications in a whole host of cardiovascular conditions that may prove efficacious in clinical trials,” said Cashman in a press release. “As antiarrhythmic drug candidate drug development progresses, we expect the new analogs to be less toxic than current therapeutics for arrhythmia in congenital heart disease, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”

The team hopes that their study can pave the way for future research in which cells in a dish can be used to lessen the toxicity of a potential drug candidate while still producing a desired result for different diseases and conditions.

The full study was published in ACS Publications.

Precision guided therapy from a patient’s own cells

/ Kevin McCormack / 1 Comment

Dr. Wesley McKeithan, Stanford

Imagine having a tool you could use to quickly test lots of different drugs against a disease to see which one works best. That’s been a goal of stem cell researchers for many years but turning that idea into a reality hasn’t been easy. That may be about to change.

A team of CIRM-funded researchers at the Stanford Cardiovascular Institute and the Human BioMolecular Research Institute in San Diego found a way to use stem cells from patients with a life-threatening heart disease, to refine an existing therapy to make it more effective, with fewer side effects.

The disease in question is called long QT syndrome (LQTS). This is a heart rhythm condition that can cause fast, chaotic heartbeats. Some people with the condition have seizures. In some severe cases, particularly in younger people, LQTS can cause sudden death.

There are a number of medications that can help keep LQTS under control. One of these is mexiletine. It’s effective at stabilizing the heart’s rhythm, but it also comes with some side effects such as stomach pain, chest discomfort, drowsiness, headache, and nausea.

The team wanted to find a way to test different forms of that medication to see if they could find one that worked better and was safer to take. So they used induced pluripotent stem cells (iPSCs) from patients with LQTS to do just that.

iPSCs are cells that are made from human tissue – usually skin – that can then be turned into any other cell in the body. In this case, they took tissue from people with LQTS and then turned them into heart cells called cardiomyocytes, the kind affected by the disease. The beauty of this technique is that even though these cells came from another source, they now look and act like cardiomyocytes affected by LQTS.

Dr. Mark Mercola, Stanford

In a news release Stanford’s Dr. Mark Mercola, the senior author of the study, said using these kinds of cells gave them a powerful tool.

“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. 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 researchers then used these man-made cardiomyocytes to test various drugs that were very similar in structure to mexiletine. They were looking for ones that could help stabilize the heart arrhythmia but didn’t produce the unpleasant side effects. And they found some promising candidates.

Study first author, Dr. Wesley McKeithan, says the bigger impact of the study is that they were able to show how this kind of cell from patients with a particular disease can be used to “guide drug development and identify better 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.”

The study is published in the journal Cell Stem Cell.