Beating balls of heart cells created from skin biopsies of children with a rare inherited disorder called Timothy syndrome replicate the abnormal heart rhythms that characterize the disease. The cells provide a new way to search for drugs to treat the disease, which is linked to autism and serious—sometimes fatal—heart problems.
Researchers have already identified one compound that normalizes heart rhythms in cells growing in a dish. In addition to benefiting research into Timothy syndrome, the cells might be useful for detecting drug compounds that trigger or exacerbate abnormal heart rhythms, one of the most common reasons for drugs to be pulled off the market.
The findings, published Thursday in Nature, are part of a growing trend to create stem cells from patients with specific diseases, such as heart disease, neurodegenerative disorders, and developmental disorders, and use these cells to recreate the disease of interest in a dish. Although scientists have previously created cells from people with Down syndrome, ALS, diabetes, and inherited forms of heart disease related to Timothy syndrome, this study is among the first to use the cells to screen compounds intended to reverse the defects seen in the cells.
“Even though we know the gene mutation for many of these diseases, people haven’t always connected the dots in terms of how the mutation leads to the arrhythmia [abnormal heart rhythm],” says Michael Laflamme, a physician-scientist in the Center for Cardiovascular Biology at the University of Washington, who was not involved in the study. “That’s where these cells come in.”
Ricardo Dolmetsch, a neurobiologist at Stanford, and collaborators collected skin cells from two young patients with Timothy syndrome and returned them to a stem-cell state with a technique called induced pluripotent stem (iPS) cell reprogramming. Like embryonic stem cells, iPS cells can be differentiated into any type of tissue, making them a potential source of tissue for drug screening and perhaps tissue-replacement therapies.
The researchers treated the stem cells with chemicals to prod them to develop into heart tissue. After growing for about a month in a dish, the cells developed into beating masses of tissue made of each of the three cell types in the heart; atrial, ventricular, and nodal cells. When the cells are made from people with normal hearts, “they beat beautifully at 60 beats per minute, just like human hearts,” says Dolmetsch. However, when derived from stem cells created from patients with cardiac disease, they beat more slowly and missed certain beats, he says. “Something is clearly wrong with them.”
By analyzing how individual cells within the balls contract, researchers discovered that the defect was limited to the ventricular cells, which form the part of the heart that pumps blood to the body. These cells had an abnormally long contraction, similar to patterns seen in patients with the disorder.
Children with Timothy syndrome typically get a pacemaker implant to keep their heart functioning properly. But many go undiagnosed and die unexpectedly in childhood or adolescence. No drugs are currently approved to treat the heart problems that accompany the disorder.
The new work is important because it can be hard to recreate cardiac problems in research animals. A mouse’s heart rate, for example, is around 500 beats per minute, while ours is only 60. When Dolmetsch’s team created a mouse with the same genetic mutation that underlies Timothy syndrome, the rodent’s heart rhythm had no abnormalities, probably because the mouse heart employs different mechanisms to keep beating so fast.
Having confirmed that the cells mimic the specific cardiac defects seen in Timothy syndrome, researchers then used them to screen different compounds known to affect heart rhythm. They found one compound, currently in clinical trials for cancer, that could partially correct the abnormal activity.
However, Dometsch cautions that this particular compound isn’t a likely candidate to be used as a drug, because it has other effects in the body. “But it could be the lead compound for an interesting new class of anti-arrhythmics,” he says. The scientist is now forming a company that will use this screening approach to develop new drugs.
Kenneth Chien, director of the Cardiovascular Research Center at Massachusetts General Hospital, says the findings demonstrate that the technology has potential for screening drugs for cardiac diseases. But he is more pessimistic about prospects specifically for Timothy syndrome. Drugs that target abnormal ventricular rhythms “have often done more harm than good,” says Chien, who was not involved in the study. “That’s why most of the current therapeutic approach for managing these arrhythmias is implantable defibrillators.”
Several companies have sprung up in the last few years with the aim of using iPS-derived cells to study disease and test drugs. Cellular Dynamics, a startup cofounded by stem-cell pioneer James Thomson, sells iPS-derived heart cells made from healthy people to pharmaceutical companies and others for toxicity screening. These companies will use the cells to determine whether experimental compounds could harm the heart.
Dolmetsch is also looking beyond the heart; the main focus of his lab is on neurodevelopmental disorders, such as autism. His team has collected cells from patients with a variety of disorders and is differentiating those cells into neural tissue in order to explore the specific neural defects. (A number of these disorders are also linked to cardiac defects—hence the current research.)
Dolmetsch cautions parents not to overinterpret his findings. “I am sure parents will read this, and we have to temper their expectations,” he says. “There are lots of obstacles to overcome before you can try this in patients.”