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.
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.
The Stem Cellar 
LQTS is typically an inherited genetic disease which is characterised by autosomal dominant manner. However, there is an exception in LQTS associated with sensorneural deafness, known as Jervell and Lange Nelson Syndrome which are caused by autosomal recessive manner. Most individuals diagnosis with LQTS have affected parents. Genetic analysis showed that one or more of the fifteen genes are associated with LQTS. There are three genes KCNH2, KCNQ1 and SCN5A which most commonly occurred in LQTS patients. Study in families who are meeting the clinical diagnosistic criteria for LQTS showed that 20% of families do not have detectable of pathogenic variants in a known gene. Whereas LQTS associated with biallelic pathogenic variants or heterozygosity for pathogenic variants in the difference genes (digenic pathogenic variants) is generally associated with more severe phenotype.
Current research to isolatie the skin cells from LQTS patient and induce them with iPSc to produce cardiomycytes organoids. The human diseases model is used to study the efficacy and safety of Mexilentine and analogs to treat LQTS patient. Since LQTS is genetic inherited disease, both young and old patients have irregular heart rhythm condition and fast chaotic heartbeat. Therefore, both early and mature culture also express genotype and phenotype of LQTS disease. The iPSCs-CMs patient can be used to screen in a wide variety of new drugs to determine the effectiveness and optimum of medication for an individual. In addition, genetic analysis to determine the specific gene and number of genes are involved in LQTS may provide an important guideline to improve the therapeutic efficiency of medicine. To note, an individual with tailor match medication is an alternative treatment to potentially improve safety and efficacy of medication for LQTS.