Many children are born with pre-existing heart conditions the cause pain and grief to the children, and also parents and caretakers. However, in Northern California, scientists at Stanford University have been able to replicate the specific heart defect using skin cells from the young patients, thus identifying the genetic variant efficiently. These newly formed heart cells make it fairly easy to examine the root of the cardiac problems and determine a corrective course of action if possible. In addition, their also has been a promising drug, roscovitine, identified that may reverse heart malfunctions. This will be the first of its kind for this necessary compound treatment.
Ricardo Dolmetsch, PhD, associate professor of neurobiology and senior author of the study states:

“This may be the first time this noninvasive ‘disease-in-a-dish’ technique has been used successfully to screen for drugs in heart disorders.”

Epidermic cells are converted to heart cells in a dish by reprogramming them to an embryonic-stem-cell-like state, so that the cells are capable of “differentiating” into a multitude of cell types.

Heart chamber coordination is mediated by electrical signals from cardiac nodes, much in the same way an automobile engine fires pistons. Over a dozen genetic mutations identified in humans are known to cause disruptions in this signaling pattern, resulting in a condition called long QT syndrome. LQTS is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes (TDP, a form of irregular heartbeat that originates from the ventricles). These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation. Episodes may be provoked by various stimuli, depending on the subtype of the condition.

The condition is so named because of the appearances of the electrocardiogram (ECG/EKG), on which there is prolongation of the QT interval. In some individuals the QT prolongation only occurs after the administration of certain medications.

LQTS is hard to treat because of the many side effects resulting from several approved medications. Vioxx for example (rofecoxib) was removed from the market in December 2006. Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.

Merck voluntarily withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of $2.5 billion from Vioxx.

The study marks an exciting use of iPS cells, a relatively new technology that was introduced to the medical community in the last five years. Dolmetsch and his associates reprogrammed skin cells from two Timothy syndrome patients and five normal individuals first into iPS cells, then into cardiomyocytes. Three distinct varieties of cardiomyocytes were generated in this way from both diseased as well as normal subjects. The three cell subtypes spontaneously clumped into miniature heart-like organs resembling a one-chambered heart.

Timothy syndrome is a rare autosomal dominant disorder characterized by physical malformations, as well as neurological and developmental defects, including heart QT-prolongation, heart arrhythmias, structural heart defects, syndactyly (webbing of fingers and toes) and autism spectrum disorders.

It was apparent that, in contrast to the average 60 beats per minute derived from normal subjects’ skin cells, those of Timothy syndrome patients beat at about a 30-per-minute rate and showed substantial irregularities. The investigators dissected these tiny organs into their constituent cells and showed that each was composed of atrial, ventricular and nodal cells.

Dolmetsch continues:

“We found that their ventricular cells, although not their atrial or nodal cells, had impaired calcium flow compared with like cells from normal subjects.”

The investigators examined the response of these irregular-beating cells to different drugs that have been reported to affect heartbeat rhythms. When they added one of these drugs, roscovitine, currently in clinical trials for an unrelated indication, to the cell-culture medium at the right dose, the deficient calcium flow was restored, and so was the regular heartbeat.

Dolmetsch cautioned that at this point roscovitine should not be considered an adequate treatment for LQTS and it hasn’t been tested for this purpose in living animals, let alone humans, and may have pronounced side effects. Still, he said, it’s a promising compound for further drug development. Stanford’s Office of Technology Licensing has applied for U.S. patents related to the discovery, and Dolmetsch is starting a new company that intends to license those patents once they’re granted.

Roscovitine (Seliciclib or CYC202) is a trial drug in the family of pharmacological cyclin-dependent kinase (CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the growth phase or state within the cell cycle of treated cells. Seliciclib is being developed by Cyclacel.

Source: Nature International Weekly Journal of Science

Written by Sy Kraft, B.A.